Novel human NK3 receptor-selective antagonist compounds, method for obtaining them and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I), a method for obtaining them and pharmaceutical compositions containing them are described. The compounds are useful as human NK 3  receptor antagonists.

[0001] The present invention relates to novel selective human NK₃receptor antagonist compounds for the preparation of drugs useful in thetreatment of psychiatric diseases, diseases of psychosomatic origin,hypertension and, in general, any central or peripheral pathologicalcondition in which neurokinin B and the NK₃ receptor are involved in theinterneuronal regulatory processes, to a method of obtaining saidcompounds and to the pharmaceutical compositions in which they arepresent as the active principle.

[0002] Diseases of psychosomatic origin are understood as meaningdiseases which originate in the central nervous system (CNS) and havepathological consequences on the peripheral nervous system.

[0003] In recent years, numerous research studies have been carried outon tachykinins and their receptors. Tachykinins are distributedthroughout both the central nervous system and the peripheral nervoussystem. The tachykinin receptors have been recognized and are classifiedinto three types: NK₁, NK₂, NK₃. Substance P (SP) is the endogenousligand of the NK₁ receptors, neurokinin A (NK_(A)) that of the NK₂receptors and neurokinin B (NK_(B)) that of the NK₃ receptors.

[0004] The NK₁, NK₂ and NK₃ receptors have been identified in differentspecies. Thus the NK₃ receptors have been identified in the guinea-pig,the rat and the monkey (Br. J. Pharmacol., 1990, 99, 767- 773);Neurochem. Int., 1991, 18 149-165); they have also been identified inman (FEBS Letters, 1992, 299 (1), 90-95).

[0005] A review by C. A. Maggi et al. looks at the tachykinin receptorsand their antagonists and gives an account of the pharmacologicalstudies and the applications in human therapeutics (J. AutonomicPharmacol., 1993, 13, 23-93).

[0006] The following non-peptide compounds may be mentioned among thespecific NK₁ receptor antagonists: CP-96345 (J. Med. Chem., 1992, 35,2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212)and SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).

[0007] In the case of the NK₂ receptor, the non-peptide selectiveantagonist SR 48968 has been described in detail (Life Sci., 1992, 50,PL101-PL106).

[0008] As far as the human NK₃ receptor is concerned, the non-peptideselective antagonist(+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamidehydrochloride, or SR 142801, has been described (EP-A-0 673 928;Peptides and their antagonists in tissue injury, Montreal, Canada, Jul.31, 1994-Aug. 3, 1994. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl.2), 25, Abst. III. 0. 9.; Life Sci., 1994, 56 (1), 27-32; BritishPharmacol. Society, Canterbury, Apr. 6-8, 1995; Eur. J. Pharmacol.,1995, 278 (1), 17-25; 1st Eur. Congress Pharmacol., Milan, Jun. 16-19,1995).

[0009] Patent applications EP 474 561 and EP 512 901 describe neurokininantagonists, more particularly NK₁ or NK₂ receptor antagonists.Pharmacological studies of peptide and non-peptide NK₁ and NK₂ receptorantagonists have shown that their affinities for these receptors, andtheir pharmacological activities, are very dependent on the species;this is very probably the result of small differences in the amino acidsequences, inducing very slight structural variations in these receptorsfrom one species to another (J. Autonomic Pharmacol., 1993, 13 23-93).Some experimental data, confirmed by pharmacological characterization ofthe compounds forming the subject of the present invention, seemtoindicate that a comparable situation exists for the NK₃ receptor. Inparticular, the human NK₃ receptor differs from the NK₃ receptor of therat.

[0010] Non-peptide compounds have now been found which have a verystrong affinity for the human NK₃ receptor and a high specificity forsaid receptor. These compounds can be used for the preparation of drugsuseful in the treatment of psychiatric diseases, diseases ofpsychosomatic origin and any central or peripheral diseases in whichneurokinin B and the NK₃ receptor are involved in the interneuronalregulatory processes.

[0011] Very strong affinity for the human NK₃ receptor is understood asmeaning an affinity characterized by an inhibition constant Ki which isgenerally less than 5.10⁻⁹ M.

[0012] In ligand binding studies, the inhibition constant Ki is definedby the Cheng-Prusoff relationship (in Receptor Binding in Drug Research,eds. R. A. O'BRIEN. Marcel Dekker, New York, 1986):${Ki} = \frac{{IC}_{50}}{1 + \frac{\lbrack L\rbrack}{Kd}}$

[0013] [L]: concentration of the ligand,

[0014] Kd: dissociation constant of the ligand,

[0015] IC₅₀: concentration which inhibits ligand binding by 50%.

[0016] High specificity for the human NK₃ receptor is understood asmeaning that the inhibition constant (Ki) for the human NK₃ receptor isgenerally at least 100 times lower than the inhibition constant (Ki) forthe NK₂ receptor or the inhibition constant for the NK₁ receptor ofdifferent species.

[0017] Thus, according to one of its aspects, the present inventionrelates to compounds of the formula

[0018] in which:

[0019] R₁ is hydrogen;

[0020] R₂ is the methyl group;

[0021] or R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0022] Ar₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; athienyl which is unsubstituted or substituted by a halogen atom; abenzothienyl which is unsubstituted or substituted by a halogen atom; anaphthyl which is unsubstituted or substituted by a halogen atom; anindolyl which is unsubstituted or N-substituted by a (C₁-C₄)alkyl or abenzyl; an imidazolyl which is unsubstituted or substituted by a halogenatom; a pyridyl which is unsubstituted or substituted by a halogen atom;or a biphenyl;

[0023] T is a group —CH₂—; a group —CO—; a group —COO—; or a group—CONR₃— in which R₃ is a hydrogen or a (C₁-C₄)alkyl;

[0024] A is a direct bond; a group —(CH₂)_(t)—, in which t is one, twoor three; or a vinylene group;

[0025] or —T—A— is the group —SO₂—;

[0026] Z is an optionally substituted, mono-, di- or tri-cyclic aromaticor heteroaromatic group; and

[0027] B is:

[0028] i—either a group B₁ of the formula

[0029] in which J₁ is:

[0030] i₁ either a group

[0031] in which:

[0032] x is zero or one;

[0033] Ar₂ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a nitro,a hydroxyl, a trifluoromethyl, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy and amethylenedioxy, said substituents being identical or different; apyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstitutedor substituted by a (C₁-C₄)alkyl; and

[0034] X₁ is a group selected from:

[0035] (1) hydrogen;

[0036] (2) (C₁-C₇)alkyl;

[0037] (3) formyl;

[0038] (4) (C₁-C₇)alkylcarbonyl;

[0039] (5) —(CH₂)_(m)—OR₄;

[0040] (6) —(CH₂)_(m)—OCOR₅;

[0041] (7) —(CH₂)_(m)—OCONH—(C₁-C₇)alkyl;

[0042] (8) —O—CH₂CH₂—OR₆;

[0043] (9) —(CH₂)_(n)—SR₇;

[0044] (10) —CH₂—S(O)_(j)—(C₁-C₇)alkyl;

[0045] (11) —NR₈R₉;

[0046] (12) —(CH₂)_(p)—NR₁₀R₁₁;

[0047] (13) —NR₁₂COR₁₃;

[0048] (14) —NR₄COCOR₁₅;

[0049] (15) —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆;

[0050] (16) —(CH₂)_(m)—NR₁₄COOR₁₇;

[0051] (17) —(CH₂)_(m)—NR₁₄SO₂R₁₈;

[0052] (18) —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀;

[0053] (19) —(CH₂)_(n)—COOR₂₁;

[0054] (20) —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀;

[0055] (21) —CO—NR₂₂—NR₂₃R₂₄;

[0056] (22) —CN;

[0057] or X₁ forms a double bond between the carbon atom to which it isbonded and the adjacent carbon atom of the piperidine ring;

[0058] in which groups:

[0059] m is zero, one or two;

[0060] n is zero or one;

[0061] p is one or two;

[0062] j is one or two;

[0063] W₁ is an oxygen atom or a sulfur atom;

[0064] R₄ is a hydrogen or a (C₁-C₇)alkyl;

[0065] R₅ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; or apyridyl;

[0066] R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl;

[0067] R₇ is a hydrogen or a (C₁-C₇)alkyl;

[0068] R₈ and R₉ are each independently a hydrogen or a (C₁-C₇)alkyl; R₉can also be a (C₃-C₇)cycloalkylmethyl, a benzyl or a phenyl;

[0069] or R₈ and R₉, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0070] R₁₀ and R₁₁ are each independently a hydrogen or a (C₃-C₇)alkyl;R₁₁ can also be a (C₃-C₇)cycloalkylmethyl or a benzyl;

[0071] R₁₂ is a hydrogen or a (C₁-C₇)alkyl;

[0072] R₁₃ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

[0073] or R₁₂ and R₁₃ together are a group —(CH₂)_(u)—, in which u isthree or four;

[0074] R₁₄ is a hydrogen or a (C₁-C₇)alkyl;

[0075] R₁₅ is a (C₁-C₄)alkoxy;

[0076] R₁₆ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

[0077] R₁₇ is a (C₁-C₇)alkyl or a phenyl;

[0078] R₁₈ is a (C₁-C₇)alkyl; an amino which is free or substituted byone or two (C₁-C₇)alkyls; or a phenyl which is unsubstituted ormonosubstituted or poly-substituted by a substituent selected from ahalogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, a hydroxyl, a(C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a(C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, said substituents beingidentical or different;

[0079] R₁₉ and R₂₀ are each independently a hydrogen or a (C₁-C₇)alkyl;R₂₀ can also be a (C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; ahydroxyl; a (C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkylsubstituted by a hydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a(C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted orsubstituted by one or two (C₁-C₇)alkyls;

[0080] or R₁₉ and R₂₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0081] R₂₁ is a hydrogen or a (C₁-C₇)alkyl;

[0082] R₂₂ is a hydrogen or a (C₁-C₇)alkyl;

[0083] R₂₃ and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

[0084] R₂₅ is a hydrogen or a (C₁-C₇)alkyl; and

[0085] R₂₆ and R₂₇ are each independently a hydrogen or a (C₁-C₇)alkyl;R₂₇ can also be a formyl or a (C₁-C₇)alkylcarbonyl;

[0086] in which Ar₂ is as defined above;

[0087] in which Ar₂ is as defined above;

[0088] in which Ar₂ is as defined above;

[0089] in which:

[0090] Ar₂ is as defined above;

[0091] Am₁ is an amino group substituted by two (C₁-C₄)alkyls; and

[0092] r is two or three;

[0093] in which:

[0094] Ar₂ is as defined above;

[0095] W₂ is an oxygen atom; a sulfur atom; a sulfinyl; a sulfonyl; or agroup —NL₁—;

[0096] L₁ is a hydrogen; a (C₁-C₄)alkyl; a (C₁-C₄)alkylcarbonyl; or agroup —(CH₂)_(v)— Am₂;

[0097] v is one, two or three; and

[0098] Am₂ is an amino group which is unsubstituted or monosubstitutedor disubstituted by a (C₁-C₄)alkyl; Am₂ can also be a pyrrolidino,piperidino or morpholino group;

[0099] ii—or a group B₂ of the formula

[0100] in which J₂ is:

[0101] in which:

[0102] Ar₂ is as defined above;

[0103] r is two or three; and

[0104] Am₁ is as defined above;

[0105] iii—or a group B₃ of the formula

[0106] in which J₃ is:

[0107] in which:

[0108] W₃ is an oxygen atom; a sulfur atom; or a group NR₃₀, in whichR₃₀ is a hydrogen or a (C₁-C₃)alkyl;

[0109] R₂₈ is a hydrogen; a (C₁-C₆)alkyl; a (C₃-C₆)alkenyl in which onevinylic carbon atom is not bonded to the nitrogen atom; a2-hydroxyethyl; a (C₃-C₇)cycloalkyl; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a trifluoromethyl, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, anitro, an amino and a hydroxyl, said substituents being identical ordifferent; or a 6-membered heteroaryl containing one or two nitrogenatoms as heteroatoms, said heteroaryl being unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a trifluoromethyl, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, anitro, an amino and a hydroxyl, said substituents being identical ordifferent;

[0110] R₂₉ is a hydrogen; a (C₁-C₆)alkyl which is unsubstituted orsubstituted by a hydroxyl and/or by one, two or three fluorine atoms; a(C₃-C₆)cycloalkyl; a (C₁-C₅)alkoxy (only when W₃ is an oxygen atom); a(C₃-C₆)cycloalkoxy (only when W₃ is an oxygen atom); or a group —NR₃₁R₃₂containing from zero to seven carbon atoms, R₂₉ being other than anunsubstituted (C₁-C₄)alkyl when simultaneously W₃ is an oxygen and R₂₈is a phenyl which is unsubstituted or monosubstituted or polysubstitutedby a substituent selected from a halogen atom, a nitro, a hydroxyl, atrifluoromethyl, a (C₁-C₄)alkyl and a (C₁-C₄)alkoxy, said substituentsbeing identical or different; a pyridyl; or a pyrimidyl;

[0111] or R₂₈ and R₂₉ together form a divalent hydrocarbon group L₂, inwhich the 1-position is bonded to the carbon atom carrying thesubstituent W₃, the divalent hydrocarbon group L₂ being selected from atrimethylene, a cis-propenylene, a tetramethylene, a cis-butenylene, acis,cis-butadienylene, a pentamethylene and a cis-pentenylene, saiddivalent hydrocarbon group L₂ being unsubstituted or substituted by oneor two methyls; and

[0112] R₃₁ and R₃₂ are each independently a hydrogen, a (C₁-C₅)alkyl ora (C₃-C₆)cycloalkyl; or R₃₁ and R₃₂, together with the nitrogen atom towhich they are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0113] iv—or a group B₄ of the formula

[0114] in which:

[0115] W₄ is a (C₁-C₈)alkyl or a (C₃-C₈)cycloalkyl, said alkyl andcycloalkyl groups being unsubstituted or substituted by one or moresubstituents selected from a halogen atom; a (C₃-C₆)cycloalkyl; a cyano;a nitro; a hydroxyl; a (C₁-C₄)alkoxy; a formyloxy; a(C₁-C₄)alkylcarbonytoxy; an arylcarbonyl; a heteroarylcarbonyl; an oxo;an imino which is unsubstituted or substituted on the nitrogen atom by a(C₁-C₆)alkyl, a (C₃-C₆)cycloalkyl, a formyl, a (C₁-C₄)alkylcarbonyl oran arylcarbonyl; a hydroxyimino which is unsubstituted or substituted onthe oxygen atom by a (C₁-C₄)alkyl or a phenyl; a group —NR₃₃R₃₄containing from zero to seven carbon atoms; a group —NR₃₅R₃₆; a group—C(═NR₃₇)NR₃₈R₃₉, in which the group —NR₃₈R₃₉ contains from zero toseven carbon atoms; and a group —CON(OR₄₀)R₄₁, said substituents beingidentical or different;

[0116] R₃₃ and R₃₄ are each independently a hydrogen, a (C₁-C₅)alkyl ora (C₃-C₆)cycloalkyl; or R₃₃ and R₃₄, together with the nitrogen atom towhich they are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0117] R₃₅ is a hydrogen or a (C₁-C₄)alkyl;

[0118] R₃₆ is a formyl; a (C₁-C₄)alkylcarbonyl; an arylcarbonyl; aheteroarylcarbonyl; or a group —C(═W₅)NR₃₈R₃₉, in which the group—NR₃₈R₃₉ contains from zero to seven carbon atoms;

[0119] W₅ is an oxygen atom; a sulfur atom; a group NR₃₇; or a groupCHR₄₂;

[0120] R₃₇ is a hydrogen or a (C₁-C₄)alkyl; or R₃₇ and R₃₉ together forman ethylene group or a trimethylene group;

[0121] R₃₈ and R₃₉ are each independently a hydrogen, a (C₁-C₅)alkyl ora (C₃-C₆)cycloalkyl; or R₃₈ and R₃₉, together with the nitrogen atom towhich they are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; or R₃₈ is a hydrogen or a (C₁-C₄)alkyl and R₃₉ and R₃₇together form an ethylene group or a trimethylene group;

[0122] R₄₀ and R₄₁ are each independently a (C₁-C₃)alkyl;

[0123] R₄₂ is a cyano; a nitro; or a group SO₂R₄₃,

[0124] R₄₃ is a (C₁-C₄)alkyl or a phenyl; and when W₄ is a cyclic groupor when a substituent of W₄ is a cyclic group or contains a cyclicgroup, said cyclic groups can also be substituted on a carbon atom byone or more (C₁-C₃)alkyls; and when a substituent of W₄ contains an arylgroup or a heteroaryl group, said aryl or heteroaryl groups can also bemonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a cyano, atrifluoromethyl and a nitro, said substituents being identical ordifferent;

[0125] v—or a group B₅ of the formula

[0126] in which:

[0127] W₆ and W₇ are each a hydrogen; or W₆ is a hydrogen and W₇ is ahydroxyl;

[0128] W₈ is an aryl or a heteroaryl which are unsubstituted orsubstituted by an aryl, an arylcarbonyl, a heteroaryl or aheteroarylcarbonyl; said aryl or heteroaryl groups can also bemonosubstituted or polysubstituted on the aromatic or heteroaromaticmoiety and on a carbon atom by a substituent selected from a halogenatom; a cyano; a trifluoromethyl; a nitro; a hydroxyl; a (C₁-C₅)alkoxy;a formyloxy; a (C₁-C₄)alkylcarbonyloxy; a group —NR₃₃R₃₄ containing fromzero to seven carbon atoms; a group —NR₃₅R₃₆; a group —C(═NR₃₇)NR₃₈R₃₉,in which the group —NR₃₈R₃₉ contains from zero to seven carbon atoms; agroup —COOR₄₄; a group —CONR₄₅R₄₆, in which the group NR₄₅R₄₆ containsfrom zero to seven carbon atoms; a mercapto; a group —S(O)_(S)R₄₇; a(C₁-C₅)alkyl; a formyl; and a (C₁-C₄)alkylcarbonyl, said substituentsbeing identical or different; when W₆ and W₇ are each a hydrogen, W₈ isother than a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a nitro,a hydroxyl, a trifluoromethyl and a (C₁-C₄)alkoxy, said substituentsbeing identical or different; a pyridyl; a thienyl; a pyrimidyl; or animidazolyl which is unsubstituted or substituted by a (C₁-C₄)alkyl;

[0129] or W₇ is a hydrogen and W₆ and W₈, together with a diradical W₉and the piperidine carbon atom to which they are bonded, form a spiroring in which W₈ is a phenyl substituted in the ortho position by adiradical W₉, which is itself joined to W₆, said phenyl beingunsubstituted or substituted by a substituent selected from a halogenatom, a (C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a hydroxyl, a (C₁-C₃)alkylthio, a(C₁-C₃)alkylsulfinyl and a (C₁-C₃)alkylsulfonyl; the diradical W₉ is amethylene, a carbonyl or a sulfonyl; and W₆ is an oxygen atom or a group—NR₄₈—, in which R₄₈ is a hydrogen or a (C₁-C₃)alkyl;

[0130] R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈ and R₃₉ are as defined above for thegroup B₄;

[0131] R₄₄ is a hydrogen; a (C₁-C₅)alkyl; an aryl; a heteroaryl; anarylmethyl; or a heteroarylmethyl;

[0132] R₄₅ and R₄₆ are each independently a hydrogen, a (C₁-C₅)alkyl ora (C₃-C₆)cycloalkyl; or R₄₅ and R₄₆, together with the nitrogen atom towhich they are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0133] s is zero, one or two;

[0134] R₄₇ is a (C₁-C₆)alkyl; a (C₃-C₆)cycloalkyl; an aryl; or aheteroaryl; and when W₈ or a substituent of W₈ contains a cyclic group,said cyclic group can also be substituted by one or more methyls; andwhen a heteroaryl group forming part of W₈ or of a substituent of W₈contains a nitrogen atom as the heteroatom, said nitrogen atom can alsobe substituted by a (C₁-C₅)alkyl; and when W₈ or a substituent of W₈contains a (C₁-C₅)alkyl, (C₁-C₅)alkoxy, formyl or (C₁-C₄)-alkylcarbonylgroup, said (C₁-C₅)alkyl, (C₁-C₅)alkoxy, formyl or (C₁-C₄)alkylcarbonylgroups can also be substituted by a hydroxyl, a (C₁-C₃)alkoxy or one ormore halogen atoms, with the proviso that a carbon atom bonded to anitrogen atom or to an oxygen atom is not substituted by a hydroxyl oran alkoxy group, and with the proviso that a carbon atom in theα-position of a (C₁-C₄)alkylcarbonyl group is not substituted by achlorine, bromine or iodine atom;

[0135] vi—or a group B₆ of the formula

[0136] in which J₄ is:

[0137] in which:

[0138] W₁₀ is a phenyl which is unsubstituted or monosubstituted totrisubstituted by a substituent selected from a halogen atom, a(C₁-C₆)alkoxy, a (C₁-C₆)alkyl and a trifluoromethyl, said substituentsbeing identical or different; a benzyl which is unsubstituted ormonosubstituted to trisubstituted by a substituent selected from ahalogen atom, a (C₁-C₆)alkoxy, a (C₁-C₆)alkyl and a trifluoromethyl,said substituents being identical or different; a naphthyl which isunsubstituted or monosubstituted to trisubstituted by a substituentselected from a halogen atom, a (C₁-C₆)alkoxy, a (C₁-C₆)alkyl and atrifluoromethyl, said substituents being identical or different; apyridyl which is unsubstituted or monosubstituted or disubstituted by asubstituent selected from a halogen atom, a (C₁-C₆)alkyl and a(C₁-C₆)alkoxy, said substituents being identical or different; athienyl; a pyrimidyl; or an imidazolyl; and

[0139] in which:

[0140] R₅₀ is a hydrogen, a (C₁-C₆)alkyl or a benzyl; and

[0141] R₅₁ is from one to three substituents selected from a hydrogen, ahalogen atom, a trifluoromethyl, a (C₁-C₆)alkyl and a (C₁-C₆)alkoxy,said substituents being identical or different;

[0142] vii—or a group B₇ of the formula

[0143] in which:

[0144] f and g are each independently zero, one, two, three, four orfive, with the proviso that f+g is equal to one, two, three, four orfive;

[0145] W₁₂ is a direct bond; a (C₁-C₃)alkylene which is unsubstituted orsubstituted by an oxo, a group OR₅₂, a halogen, a trifluoromethyl or aphenyl which is itself unsubstituted or mono-, di- or tri-substituted bya substituent selected from a hydroxyl, a cyano, a halogen and atrifluoromethyl; a group —S(O)_(k)—; a group (C₁-C₃)alkylene-S(O)_(k)—;a group —S(O)_(k)—(C₁-C₂)alkylene; a group —S(O)_(k)—NH—; a group—S(O)_(j)—NR₅₂—; a group —S(O)_(j)—NR₅₂—(C₁-C₂)alkylene; a group—CONR₅₂—; a group —CONR₅₂—(C₁-C₂)alkylene; a group —COO—; or a group—COO—(C₁-C₂)alkylene;

[0146] W₁₃ is a group —NR₅₃—; an oxygen atom; a sulfur atom; a sulfinyl;or a sulfonyl, with the proviso that when W₁₂ is a direct bond and whenW₁₄ is a (C₁-C₃)alkylene, W₁₃ is a group —NR₅₃—;

[0147] W₁₄ is a direct bond; a (C₁-C₃)alkylene which is unsubstituted orsubstituted by an oxo, a group OR₅₂, a halogen, a trifluoromethyl or aphenyl which is itself unsubstituted or mono-, di- or tri-substituted bya substituent selected from a group OR₅₂, a halogen and atrifluoromethyl; a group —S(O)_(k)—; a group (C₁-C₃)alkylene-S(O)_(k)—;a group —S(O)_(k)—(C₁-C₂)alkylene; a group —NHS(O)_(j)—; a group—NH—(C₁-C₂)alkylene-S(O)_(j)—; a group —S(O)_(j)NR₅₂—; a group—S(O)_(j)—NR₅₂—(C₁-C₂)alkylene; a group —NHCO—(C₁-C₂)alkylene; a group—NR₅₂—CO—; a group —NR₅₂—(C₁-C₂)alkylene-CO—; a group —OCO—; or a group(C₁-C₂)alkylene-OCO—;

[0148] W₁₅-W₁₆ together forrn two adjacent atoms of a cyclic radical ofthe formula

[0149] said cyclic radical being a phenyl, a naphthyl or a heteroarylgroup selected from a benzimidazolyl, a benzofuranyl, a benzoxazolyl, afuranyl, an imidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, anoxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, apyrimidyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl, athiazolyl, a thienyl and a triazolyl, and said phenyl, naphthyl orheteroaryl cyclic radical being unsubstituted or mono-, di- ortri-substituted by R₅₄;

[0150] k is zero, one or two;

[0151] j is one or two;

[0152] R₅₂ is a hydrogen; a (C₁-C₆)alkyl which is unsubstituted ormonosubstituted or disubstituted by a substituent selected independentlyfrom a hydroxyl, an oxo, a cyano, a halogen atom, a trifluoromethyl anda phenyl which is itself unsubstituted or substituted by a hydroxyl, a(C₁-C₃)alkyl, a cyano, a halogen, a trifluoromethyl or a (C₁-C₄)alkoxy;a phenyl, a pyridyl or a thiophene, said phenyl, pyridyl or thiophenebeing unsubstituted or mono-, di- or tri-substituted by a substituentselected independently from a hydroxyl, a (C₁-C₄)alkyl, a cyano, ahalogen atom and a trifluoromethyl; or a (C₁-C₃)alkoxy;

[0153] R₅₃ is a hydrogen; a (C₁-C₈)alkyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from agroup —OR₅₂, an oxo, a group —NHCOR₅₂, a group —NR₅₅R₅₆, a cyano, ahalogen atom, a trifluoromethyl and a phenyl which is itselfunsubstituted or substituted by a hydroxyl, a cyano, a halogen atom or atrifluoromethyl; a group —S(O)R₅₇; a group —CO₂R₅₇; a group —SO₂R₅₇; agroup —COR₅₇; or a group —CONR₅₆R₅₇;

[0154] R₅₄ is a hydrogen; a (C₁-C₆)alkyl which is unsubstituted ormonosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; agroup —OR₅₂; a halogen atom; a trifluoromethyl; a nitro; a cyano; agroup —NR₅₅R₅₆; a group —NR₅₅COR₅₆; a group —NR₅₅CO₂R₅₆; a group—NHS(O)_(j)R₅₂; a group —NR55S(O)_(j)R₅₆; a group —CONR₅₅R₅₆; a group—COR₅₂; a group —CO₂R₅₂; a group —S(O)_(j)R₅₂; or a heteroaryl group,said heteroaryl being selected from a benzimidazolyl, a benzofuranyl, abenzoxazolyl, a furanyl, an imidazolyl, an indolyl, an isoxazolyl, anisothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, apyridyl, a pyrimidinyl, a pyrrolyl, a quinolyl, a tetrazolyl, athiadiazolyl, a thiazolyl, a thienyl and a triazolyl, and saidheteroaryl being unsubstituted or monosubstituted or disubstituted byR₅₈;

[0155] R₅₅ is R₅₂;

[0156] R₅₆ is R₅₂;

[0157] or R₅₅ and R₅₆, together with the atoms to which they are bonded,form a five-, six- or seven-membered, saturated monocyclic heterocyclecontaining one or two heteroatoms, said heteroatoms being selectedindependently from a nitrogen atom, an oxygen atom and a sulfur atom,said heterocycle being unsubstituted or monosubstituted or disubstitutedby a substituent selected from a hydroxyl, an oxo, a cyano, a halogenatom and a trifluoromethyl;

[0158] R₅₇ is a (C₁-C₆)alkyl which is unsubstituted or mono-, di- ortri-substituted by a substituent selected from a hydroxyl, an oxo, acyano, a group —OR₅₂, a group —NR₅₅R₅₆, a group —NR₅₅COR₅₆, a halogenatom, a trifluoromethyl and a phenyl which is itself unsubstituted ormono-, di- or tri-substituted by a substituent selected from a hydroxyl,an oxo, a cyano, a group —NHR₅₂, a group —NR₅₅R₅₆, a group —NR₅₅COR₅₆, ahalogen atom, a trifluoromethyl and a (C₁-C₃)alkyl;

[0159] R₅₈ is a hydrogen; a (C₁-C₆)alkyl which is unsubstituted ormonosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; agroup —OR₅₂; a trifluoromethyl; a nitro; a cyano; a group —NR₅₅R₅₆; agroup —NR₅₅COR₅₆; a group —NR₅₅CO₂R₅₆; a group —NHS(O)_(j)R₅₂; a group—NR₅₅S(O)_(j)R₅₆; a group —CONR₅₅R₅₆; a group —COR₅₂; a group —CO₂R₅₂; agroup —S(O)_(j)R₅₂; or a phenyl, and the group B₇ being other than thegroup B₅ when W₇ is a hydrogen and W₆ and W₈, together with a diradicalW₉ and the piperidine carbon atom to which they are bonded, form a spiroring;

[0160] viii—or a group B₈ of the formula

[0161] in which:

[0162] W₁₇ is a direct bond; a double bond; or a divalent hydrocarbonradical;

[0163] W₁₈ is a radical which is joined to the carbon atom of theheterocycle either by a single bond when W₁₇ is a double bond, or by adouble bond in the other cases;

[0164] W₁₉ is an unsubstituted or optionally substituted heteroatom;

[0165] W₂₀ is a hydrocarbon radical of which the 1-position is joined toW₁₉; and

[0166] the meanings of W₁₇, W₁₈, W₁₉ and W₂₀ are selected from:

[0167] (a) W₁₇ is a direct bond; W₁₈ is an oxo or thioxo group; W₁₉ isan oxy or thio group or a group NR₅₉; and W₂₀ is a hydrocarbon radicalL₃; or

[0168] (b) W₁₇ is a direct bond; W₁₈ is a group NR₆₀; W₁₉ is a groupNR₆₁; and W₂₀ is a hydrocarbon radical L₃; or

[0169] (c) W₁₇ is a double bond; W₁₈ is a group OR₆₁, SR₆₁ or NR₆₂R₆₃;W₁₉ is a nitrogen atom; and W₂₀ is a hydrocarbon radical L₃; or

[0170] (d) W₁₇ is a methylene which is unsubstituted or substituted byone or two methyl groups; W₁₈ is an oxo or thioxo group or a group NR₆₄;W₁₉ is an oxy, thio, sulfinyl or sulfonyl group or a group NR₆₁; and W₂₀is a hydrocarbon radical L₄; or

[0171] (e) W₁₇ is a direct bond; W₁₈ is an oxo or thioxo group or agroup NR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is a hydrocarbon radical L₅;or

[0172] (f) W₁₇ is a methine group which is unsubstituted or substitutedby one or two methyl groups; W₁₉ is an oxo or thioxo group or a groupNR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is a hydrocarbon radical L₆; and

[0173] (g) W₁₇ is a cis-vinylene group which is unsubstituted orsubstituted by one or two methyl groups; W₁₈ is an oxo or thioxo groupor a group NR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is a hydrocarbonradical L₇;

[0174] R₅₉ is a hydrogen; a (C₁-C₃)alkyl; a group —CH₂COOR₆₅; or a group—CH₂CONR₆₆R₆₇,

[0175] R₆₀ is a hydrogen; a (C₁-C₃)alkyl; a cyano; a nitro; or a(C₁-C₃)alkylsulfonyl group;

[0176] R₆₁ is a hydrogen or a (C₁-C₃)alkyl;

[0177] R₆₂ and R₆₃ are each independently a hydrogen or a (C₁-C₃)alkyl;

[0178] or R₆₂ and R₆₃, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine,morpholine, thiomorpholine (or its S-oxide) and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

[0179] R₆₄ is a hydrogen or a (C₁-C₃)alkyl;

[0180] R₆₅ is a hydrogen or a (C₁-C₃)alkyl;

[0181] R₆₆ and R₆₇ are each independently a hydrogen; a (C₁-C₃)alkyl; aphenyl; or a benzyl;

[0182] L₃ is an ethylene, a cis-vinylene, a trimethylene or atetramethylene, said hydrocarbon radical L₃ being unsubstituted orsubstituted by one or two methyl groups;

[0183] L₄ is an ethylene or a trimethylene, said hydrocarbon radical L₄being unsubstituted or substituted by one or two methyl groups;

[0184] L₅ is a prop-2-en-1-yliden-3-yl which is unsubstituted orsubstituted by one or two methyl groups;

[0185] L₆ is a cis-vinylene which is unsubstituted or substituted by oneor two methyl groups; and

[0186] L₇ is a methine which is unsubstituted or substituted by a(C₁-C₃)alkyl;

[0187] ix—or a group B₉ of the formula

[0188] in which J₅ is:

[0189] a group

[0190] in which:

[0191] X₂ is a (C₁-C₆)alkyl; a group —CH₂—OR₆₈; a group —CH₂—SR₆₈; agroup —CH₂—S(O)R₆₉; a group —CH₂—SO₂R₆₉; a group —COOR₆₈; a group—C(═W₂₄)NR₇₀R₇₁; a group —C(R₆₈)(OR₇₂)(OR₇₃); a group—CH₂NR₆₈C(═W₂₄)R₇₄; a group —CH₂—NR₆₈COOR₇₄; or a group—CH₂NR₆₈C(═W₂₄)NR₇₀R₇₁;

[0192] W₂₁ is a direct bond and W₂₂ is a hydrocarbon radical of whichthe 1-position is joined to W₂₁, the hydrocarbon radical W₂₂ beingselected from a trimethylene, a tetramethylene, a cis-1-butenylene and acis,cis-butadienylene;

[0193] or W₂₁ is a group NR₇₅ and W₂₂ is a hydrocarbon radical selectedfrom an ethylene, a trimethylene and a cis-vinylene;

[0194] or W₂₁ is a nitrogen atom and W₂₂ is acis,cis-prop-2-en-1-yliden-3-yl radical of which the 1-position isjoined to W₂₁;

[0195] W₂₃ is an oxygen atom or a sulfur atom;

[0196] W₂₄ is an oxygen atom or a sulfur atom;

[0197] R₆₈ is a hydrogen or a (C₁-C₆)alkyl;

[0198] R₆₉ is a (C₁-C₆)alkyl;

[0199] R₇₀ and R₇₁, are each independently a hydrogen; a (C₁-C₆)alkylwhich is unsubstituted or substituted by a hydroxyl or a (C₁-C₃)alkoxy;an ω—HO—(C₁-C₆)alkyl; an ω-(C₁-C₃)alkoxy-(C₁-C₆)alkyl; anωphenyl-(C₁-C₆)alkyl; an ω—R₇₆OOC—(C₁-C₆)alkyl; or anω—R₇₇R₇₈NCO—(C₁-C₆)alkyl;

[0200] or R₇₀ and R₇₁, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine,morpholine, thiomorpholine (or its S-oxide) and piperazine which isunsubstituted or substituted in the 4-position by a methyl group or anethyl group;

[0201] R₇₂ and R₇₃ are each independently a (C₁-C₃)alkyl;

[0202] or R₇₂ and R₇₃ together form a divalent hydrocarbon radicalselected from an ethylene and a trimethylene;

[0203] R₇₄ is a hydrogen or a (C₁-C₆)alkyl;

[0204] R₇₅ is a hydrogen or a (C₁-C₆)alkyl;

[0205] R₇₆ is a hydrogen or a (C₁-C₃)alkyl; and

[0206] R₇₇ and R₇₈ are each independently a hydrogen or a (C₁-C₃)alkyl;

[0207] x—or a group B₁₀ of the formula

[0208] in which J₆ is:

[0209] a group

[0210] in which:

[0211] X₁ is as defined above for the group B₁, X₁ being other thanhydrogen when W₂₅ is a (C₁-C₇)alkyl or a (C₃-C₇)cycloalkyl;

[0212] W₂₅ is a (C₁-C₇)alkyl or a (C₃-C₇)cycloalkyl; W₂₅ can also be agroup —NR₇₉R₈₀ when X₁ is a hydrogen, a cyano, a carboxyl, a(C₁-C₇)alkoxycarbonyl or a group —CONR₁₉R₂₀; and

[0213] R₇₉ and R₈₀ are each independently a (C₁-C₇)alkyl;

[0214] or R₇₉ and R₈₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine and perhydroazepine,

[0215] with the proviso that:

[0216] 1/ when simultaneously:

[0217] R₂ is a methyl group or R₁ and R₂ together form a group —(CH₂)₃—;

[0218] Ar₁ is a 3,4-dichlorophenyl;

[0219] T is a group —CH₂—; a group —CO—; a group —COO—; or a group—CONR₃;

[0220] A is a direct bond; a group —(CH₂)_(t)— in which t is one, two orthree; or a vinylene group;

[0221] or —T—A— is the group —SO₂—; and

[0222] Z is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a halogen, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy or anitro,

[0223] B is a group B₁ of the formula

[0224] in which J₁ is a group

[0225] in which:

[0226] x is zero;

[0227] Ar₂ is a pyrid-2-yl or a phenyl which is unsubstituted orsubstituted by a halogen, a methyl or a (C₁-C₄)alkoxy; and

[0228] X₁ is other than a group selected from: formyl;

[0229] (C₁-C₆)alkylcarbonyl;

[0230] —(CH₂)_(m)—OR₄ in which m is zero or one and R₄ is a hydrogen ora (C₁-C₇)alkyl;

[0231] —(CH₂)_(m)—OCOR₅ in which m is zero or one and R₅ is a hydrogenor a (C₁-C₆)alkyl;

[0232] —(CH₂)_(m)—OCONH(C₁-C₇)alkyl in which m is one;

[0233] —NR₈R₉ in which R₈ and R₉ are each independently a hydrogen or a(C₁-C₇)alkyl;

[0234] R₉ can also be a (C₃-C₇)cycloalkylmethyl, a benzyl or a phenyl;or R₈ and R₉, together with the nitrogen atom to which they are bonded,form a heterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

[0235] —(CH₂)_(p)—NR₁₀R₁₁ in which p is one and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a(C₃-C₇)cycloalkylmethyl or a benzyl;

[0236] —NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a (C₁-C₄)alkyl and R₁₃is a hydrogen, a (C₁-C₇)alkyl, a phenyl, a benzyl, a pyridyl or a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; or R₁₂ and R₁₃ together are a group —(CH₂)_(u)— in which u isthree or four;

[0237] —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁—C₄)alkyl and R₁₆ is a hydrogen, a(C₁-C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃-C₇)cycloalkyl whichis unsubstituted or substituted by one or more methyls;

[0238] —(CH₂)_(m)—NR₁₄COOR₁₇ in which m is zero or one, R₁₄ is ahydrogen or a (C₁-C₄)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl;

[0239] —(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is zero or one, R₁₄ is ahydrogen or a (C₁-C₄)alkyl and R₁₈ is a (C₁-C₇)alkyl, an amino which isfree or substituted by one or two (C₁-C₇)alkyls, or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a(C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, said substituents beingidentical or different;

[0240] —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is zero or one, W₁ is anoxygen atom, R₁₄ is a hydrogen or a (C₁-C₄)alkyl and R₁₉ and R₂₀ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₀ can also be a(C₃-C₇)cycloalkyl, a (C₃-C₇)cycloalkylmethyl, a hydroxyl, a(C₁-C₄)alkoxy, a benzyl or a phenyl; or R₁₉ and R₂₀, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine andperhydroazepine;

[0241] —(CH₂)_(n)—COOR₂, in which n is zero and R₂₁ is a (C₁-C₇)alkyl;

[0242] —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is zero, W₁ is an oxygen atomand R₁₉ and R₂₀ are as defined above; and —CN;

[0243] or X₁ does not form a double bond between the carbon atom towhich it is bonded and the adjacent carbon atom of the piperidine ring;

[0244] or Ar₂ and X₁, together with the carbon atom to which they arebonded, are other than a group of the formula

[0245] 2/ when R₁ is hydrogen, R₂ is the methyl group, Ar₁ is other than3,4-dichlorophenyl group and T—A—Z is the thenoyl group, B is the groupB ₁ in which J₁ is the group

[0246] in which x is one, Ar₂ is the phenyl group and X₁ is other thanhydrogen;

[0247] 3/ when R₁ is hydrogen, R₂ is the methyl group, Ar₁ is the3,4-dichlorophenyl group and T—A—Z is the 2,4-dichlorobenzoyl group, Bis the group B₁ in which J₁ is the group

[0248] in which x is one, Ar₂ is the phenyl group and X₁ is other thanhydrogen; or

[0249] 4/ when R₁ and R₂ together form a group —(CH₂)₃—, Ar₁ is the3,4-dichlorophenyl group and T—A—Z is the 2-(3-methoxyphenyl)acetylgroup, B is the group B₁ in which J₁ is the group

[0250] in which x is one, Ar₂ is phenyl and X₁ is other than hydrogen;and their salts, where appropriate, with mineral or organic acids.

[0251] The compounds of formula (I) according to the invention includethe optically pure isomers as well as the racemates.

[0252] It is possible to form salts of the compounds of formula (I).These salts include those with mineral or organic acids which permit asuitable separation or crystallization of the compounds of formula (I),such as picric acid, oxalic acid or an optically active acid, forexample a mandelic or camphosulfonic acid, as well as those with mineralor organic acids which form pharmaceutically acceptable salts such asthe hydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate,naphthalene-2-sulfonate, glycolate, gluconate, citrate, isethionate,benzenesulfonate and paratoluenesulfonate.

[0253] More particularly, the radical Z can be a phenyl group, which canbe unsubstituted or may contain one or more substituents.

[0254] When Z is a phenyl group, it can be monosubstituted ordisubstituted, especially in the 2,4-position but also, for example, inthe 2,3-, 4,5-, 3,4- or 3,5-position; it can also be trisubstituted,especially in the 2,4,6-position but also, for example, in the 2,3,4-,2,3,5-, 2,4,5- or 3,4,5-position, tetrasubstituted, for example in the2,3,4,5-position, or pentasubstituted.

[0255] The radical Z can also be a bicyclic aromatic group such as 1- or2-naphthyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl, in which one or morebonds can be hydrogenated, it being possible for said groups to beunsubstituted or optionally to contain one or more substituents such asalkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino,alkoxycarbonyl, thioalkyl, halogen, alkoxy and trifluoromethyl groups,in which the alkyls are C₁-C₄.

[0256] The radical Z can also be a group Z^(•) selected from pyridyl,thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl,benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl,benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl,thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl,pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl andchromanyl, in which one or more double bonds can be hydrogenated, itbeing possible for said groups to be unsubstituted or optionally tocontain one or more substituents such as alkyl, phenyl, cyano,hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl and thioalkylgroups, in which the alkyl and alkoxy groups are C₁-C₄.

[0257] In the present description the alkyl or alkoxy groups are linearor branched; halogen atom is understood as meaning a chlorine, bromine,fluorine or iodine atom.

[0258] In the present description, when B is a group B₄ or B₅, aryl isunderstood as meaning a phenyl radical or a C₉-C₁₀ ortho-fused bicycliccarbbcyclic radical in which at least one of the rings is aromatic;heteroaryl is understood as meaning either a five- or six-memberedmonocyclic aromatic heterocycle containing from one to four heteroatoms,said heteroatoms being selected from an oxygen atom, a sulfur atom and anitrogen atom, and said heterocycle being bonded by a carbon atom of thering, or an eight- to ten-membered ortho-fused bicyclic aromaticheterocycle containing from one to four heteroatoms as defined above.

[0259] In the substituents of the group Z=phenyl, (C₁-C₁₀)alkyl isunderstood as meaning for example a methyl, an ethyl, an n-propyl, anisopropyl, an n-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentylor n-pentyl, a hexyl or n-hexyl, a heptyl or n-heptyl, an octyl orn-octyl, a nonyl or n-nonyl or a decyl or n-decyl; (C₃-C₈)-cycloalkyloptionally substituted by a methyl is understood as meaning for examplea cyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, acycloheptyl or a cyclooctyl; (C₁-C₁₀)alkoxy is understood as meaning forexample a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy,an isobutoxy, a sec-butoxy, a tert-butoxy, a pentoxy, a hexyloxy, aheptyloxy, an octyloxy, a nonyloxy or a decyloxy; (C₃-₈)cycloalkoxyoptionally substituted by a methyl is understood as meaning for examplea cyclopropoxy, a cyclobutoxy, a cyclopentoxy, a 1-, 2- or3-methylcyclopentoxy, a cyclohexyloxy, a 1-, 2-, 3- or4-methylcyclohexyloxy, a cycloheptyloxy or a cyclooctyloxy;(C₁-C₁₀)alkylthio is understood as meaning for example a methylthio, anethylthio, an n-propylthio, an isopropylthio, an n-butylthio, anisobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, ahexylthio, a heptylthio, an octylthio, a nonylthio or a decylthio;(C₁-C₆)alkylcarbonyloxy is understood as meaning for example an acetoxy,a propionyloxy, a butyryloxy, a valeryloxy, a caproyloxy or aheptanoyloxy; (C₁-C₆)alkylcarbonylamino is understood as meaning forexample an acetylamino, a propionylamino, a butyrylamino, anisobutyrylamino, a valerylamino, a caproylamino or an heptanoylamino;(C₁-C₄)alkoxycarbonyl is understood as meaning for example amethoxycarbonyl, an ethoxycarbonyl, an n-propoxycarbonyl, anisopropoxycarbonyl, an n-butoxycarbonyl, an isobutoxycarbonyl, asec-butoxycarbonyl or a tert-butoxycarbonyl; and(C₃-C₇)cycloalkoxycarbonyl is understood as meaning for example acyclopropoxycarbonyl, a cyclobutoxycarbonyl, a cyclopentoxycarbonyl, acyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.

[0260] The invention relates particularly to compounds of formula (I) inwhich:

[0261] Z is Z^(•) as defined above;

[0262] R₁ and R₂ together form a group —(CH₂)₃—;

[0263] Ar₁ is a 3,4-dichlorophenyl;

[0264] T is a group —CO—;

[0265] A is a direct bond; and

[0266] B is as defined for a compound of formula (I), and their salts,where appropriate, with mineral or organic acids.

[0267] Among these compounds, those of the formula

[0268] in which:

[0269] Z^(•) is as defined above; and

[0270] B^(•) is a group of the formula

[0271] in which J^(•) is:

[0272] i^(•)—either a group of the structure

[0273] in which:

[0274] W^(•) is a phenyl or a benzyl and R₁₉ and R₂₀ are as defined fora compound of formula (J);

[0275] or W^(•) is a group —NR₇₉R₈₀ in which R₇₉ and R₈₀ are as definedfor (I) and Rk₁₉ and R₂₀ are each hydrogen;

[0276] i^(••)—or a group of the structure

[0277] in which:

[0278] R^(•) is hydrogen, a methyl group, an acetyl group, amethoxycarbonyl group, a dimethylaminocarbonyl group or amethanesulfonyl group,

[0279] and their salts, especially pharmnaceutically acceptable salts,are advantageous.

[0280] Among these compounds, those of the formula

[0281] in which:

[0282] B^(•) is as defied for a compound of formula (I^(•)); and

[0283] Z^(••) is a pyridyl, for example a 4-pyridyl, a 2-thienyl, a3-thienyl, a 2-furyl or a 3-furyl,

[0284] and their salts, especially pharmaceutically acceptable salts,are particularly advantageous.

[0285] Among, these compounds, those of the formula

[0286] in which:

[0287] Z^(••) is as defined for a compound of formula (I^(••)), andtheir salts, especially pharmaceutically acceptable salts, are of verygreat interest.

[0288] Advantageously the radical Z is a phenyl which is unsubstitutedor monosubstituted or polysubstituted by a halogen atom, moreparticularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a(C₁-C₄)alkyl, a hydroxyl or a (C₁-C₄)alkoxy; a naphthyl which isunsubstituted or monosubstituted or polysubstituted by a halogen, atrifluoromethyl, a (C₁-C₄)alkyl, a hydroxyl or a (C₁-C₄)alkoxy; apyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or animidazolyl.

[0289] The invention relates particularly to compounds of formula (I) inwhich:

[0290] Z is Z′ and is:

[0291] a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom; atrifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which isunsubstituted or monosubstituted or disubstituted by a (C₁-C₄)alkyl; abenzylamino; a carboxyl; a (C₁-C₁₀)alkyl; a (C₃-C₈)cycloalkyl which isunsubstituted or monosubstituted or polysubstituted by a methyl; a(C₁-C₁₀)alkoxy; a (C₃-C₈)cycloalkoxy which is unsubstituted ormonosubstituted or polysubstituted by a methyl; a mercapto; a(C₁-C₁₀)alkylthio; a formyloxy; a (C₁-C₆)alkylcarbonyloxy; aformylamino; a (C₁-C₆)alkylcarbonylamino; a benzoyl-amino; a(C₁-C₄)alkoxycarbonyl; a (C₃-C₇)cycloalkoxycarbonyl; a carbamoyl whichis unsubstituted or monosubstituted or disubstituted by a (C₁-C₄)alkyl;a ureido which is unsubstituted or monosubstituted or disubstituted inthe 3-position by a (C₁-C₄)alkyl or a (C₃-C₇)cycloalkyl; and a(pyrrolidin-1-yl)-carbonylamino, said substituents being identical ordifferent;

[0292] a naphthyl which is unsubstituted or monosubstituted orpolysubstituted by a halogen, a trifluoromethyl, a (C₁-C₄)alkyl, ahydroxyl or a (C₁-C₄)alkoxy; or

[0293] a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; oran imidazolyl, and their salts with mineral or organic acids.

[0294] The substituent Ar₁ is preferably a phenyl group which isadvantageously substituted by two chlorine atoms, more particularly inthe 3- and 4-positions.

[0295] According to the present invention, the preferred compounds arethose in which simultaneously:

[0296] Z is Z′;

[0297] Ar₁ is a 3,4-dichlorophenyl;

[0298] R₁ and R₂ together form a group —(CH₂)₃ or —(CH₂)₄—; and

[0299] B, T and A are as defined for a compound of formula (I), andtheir salts, especially pharmaceutically acceptable salts.

[0300] When B is a group B₃, W₃ is advantageously an oxygen or sulfuratom, R₂₈ is hydrogen, a (C₁-C₆)alkyl, a (C₃-C₇)cycloalkyl, preferablycyclohexyl, or a (C₃-C₄)alk-2-en-1-yl, preferably allyl, and R₂₉ ishydrogen, a (C₁-C₆)alkyl, a trifluoromethyl or a (C₁-C₄)alkylamino,preferably methylamino, or, only when R₂₈ is other than hydrogen, R₂₉ isa di(C₁-C₅)alkylamino, preferably dimethylamino, or R₂₈ and R₂₉ togetherare a 1,3-propylene, 1,4-butylene or cis,cis-1,4-butadienylene group.Consequently the compounds of formula (I) in which B is B₃ and W₃, R₂₈and R₂₉ are as just defined, and their salts, especiallypharmaceutically acceptable salts, are advantageous products.

[0301] The compounds of this subclass of formula (I) in whichsimultaneously:

[0302] B is a group B₃ in which:

[0303] either W₃ is oxygen, R₂₉ is a (C₁-C₄)alkyl or a trifluoromethyland R₂₈ is a (C₁-C₆)alkyl, especially an ethyl;

[0304] or W₃ is oxygen, R₂₈ is an allyl or a cyclohexyl and R₂₉ is amethyl;

[0305] or W₃ is oxygen, R₂₈ is an ethyl and R₂₉ is a methylamino or adimethylamino;

[0306] or W₃ is oxygen and R₂₈ and R₂₉ together form a 1,3-propylene,1,4-butylene or cis,cis-1,4-butadienyl group;

[0307] or W₃ is sulfur and R₂₈ and R₂₉ together form a 1,4-butylenegroup;

[0308] R¹ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0309] Ar₁ is a 3,4-dichlorophenyl;

[0310] Z═Z′; and

[0311] T and A are as defined above for a compound of formula (I), andtheir salts, especially pharmaceutically acceptable salts, areparticularly preferred.

[0312] When B is a group B₄, W₄ is advantageously a (C₁-C₈)alkyl groupsubstituted by a hydroxyl, oxo, hydroxyimino, (C₁-C₄)alkoxyimino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino or (C₁-C₄)alkoxy group or atthe same time by an oxo group and a hydroxyl or (C₁-C₄)alkoxy group or agroup —NR₃₃R₃₄. Consequently the compounds of formula (I) in which B isa group B₄ and W₄ is an alkyl group substituted by a hydroxyl, oxo,hydroxyimino, (C₁-C₄)alkoxyimino, (C₁-C₄)alkanoyloxy,(C₁-C₄)alkanoylamino or (C₁-C₄)alkoxy group or at the same time by anoxo group and a hydroxyl or (C₁-C₄)alkoxy group or a group —NR₃₃R₃₄, andtheir salts, especially pharmaceutically acceptable salts, areadvantageous products.

[0313] The compounds of this subclass of formula (I) in whichsimultaneously:

[0314] B is B₄ in which: W₄ is 1-hydroxypropyl, 1-hydroxyethyl,1-hydroxybutyl, 2-hydroxybut-2-yl, 4-hydroxyhept-4-yl, 2-hydroxyethyl,1-hydroxyiminopropyl (syn or anti), 1-methoxyiminopropyl (syn or anti),2-acetoxyethyl, 2-acetamidoethyl, carboxyl, ethoxycarbonyl orpyrrolidin-1-ylcarbonyl;

[0315] R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0316] Ar₁ is a 3,4-dichlorophenyl;

[0317] Z═Z′; and

[0318] T and A are as defined above for a compound of formula (I),

[0319] and their salts, especially pharmaceutically acceptable salts,are particularly preferred.

[0320] When B is a group B₅, W₆ is advantageously a hydrogen, W₇ is ahydroxyl and W₈ is a phenyl which is unsubstituted or substituted by amethoxy, a hydroxyl, a methylthio or a methylsulfinyl; or W₆ and W₇ arehydrogen and W₈ is a pyridyl, pyrimidyl or thienyl group substituted bya halogen, especially chlorine or fluorine, or by one of the followinggroups: cyano, trifluoromethyl, hydroxyl, (C₁-C₅)alkoxy, especiallymethoxy or ethoxy, formyloxy, (C₁-C₄)alkylcarbonyloxy, especiallyacetoxy, amino, methylamino, dimethylamino, acetamido, imidazolin-2-yl,carboxyl, methoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl, carbamoyl,N,N-dimethylcarbamoyl, pyrrolidinocarbonyl, N-methylcarbamoyl,methylthio, methylsulfinyl, methylsulfonyl, (C₁-C₄)alkyl, especiallymethyl, ethyl, propyl, butyl, isopropyl, 2-methylpropyl or tert-butyl,fornyl or (C₁-C₄)alkylcarbonyl, especially acetyl or propionyl; anindenyl, naphthyl, furyl, pyrrolyl, 1,3,4-oxadiazol-2-yl orbenz[d]isoxazol-3-yl group which is unsubstituted or substituted by oneof the substituents mentioned above for the pyridyl, pyrimidyl orthienyl groups; an imidazol-2-yl substituted by one of the substituentsmentioned above for the pyridyl, pyrimidyl or thienyl groups, except fora (C₁-C₄)alkyl; or a phenyl group substituted by one of the substituentsmentioned above for the pyridyl, pyrimidyl or thienyl groups, except forhalogens and hydroxyl, trifluoromethyl, (C₁-C₄)alkyl and (C₁-C₄)alkoxygroups; or W₇ is hydrogen and W₆ and W₈, together with a diradical W₉and the piperidine carbon atom to which they are bonded, form a spiroring in which W₈ is a phenyl substituted in the ortho position by thediradical W₉, which is itself joined to W₆, said phenyl beingunsubstituted or substituted by a methoxy, a hydroxyl, a methylthio or amethylsulfinyl; the diradical W₉ is a methylene or a carbonyl; and W₆ isan oxy group. Consequently the compounds of formula (I) in which B is B₅and W₆, W₇ and W₈ are as just defined, and their salts, especiallypharmaceutically acceptable salts, are advantageous products.

[0321] The compounds of this subclass of formula (I) in whichsimultaneously:

[0322] B is a group B₅ in which: W₇ is a hydroxyl, W₆ is a hydrogen andW₈ is a phenyl; or W₆ and W₇ are hydrogen and W₈ is selected from thefollowing groups: 5-methyl- 1,3,4-oxadiazol-2-yl,4-ethoxycarbonylimidazol-2-yl, 2-fluoropyrid-3-yl, 2-methylthiophenyl,4-methylthiophenyl, 2-methylsulfinylphenyl, 4-methylsulfinylphenyl and4-(N-methylcarbamoyl)phenyl; or W₇ is hydrogen and W₆ and W₈, togetherwith the piperidine to which they are bonded, form aspiro[isobenzofuran-1(3H),4′-piperid]-1′-yl group or a3-oxospiro[isobenzofuran-1(3H),4′-piperid]-1′-yl group;

[0323] R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0324] Ar₁ is a 3,4-dichlorophenyl;

[0325] Z═Z′; and

[0326] T and A are as defined above for a compound of formula (I),

[0327] and their salts, especially pharmaceutically acceptable salts,are particularly preferred.

[0328] Another group of preferred compounds of the invention consists ofthe compounds of formula (I) in which R₁, R₂, Ar₁, T, A and Z are asdefined above for (J) and B is the group B₆.

[0329] The particularly preferred compounds of formula (I) are those inwhich simultaneously:

[0330] B is a group B₆;

[0331] R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0332] Ar₁ is a 3,4-dichlorophenyl;

[0333] Z═Z′; and

[0334] T and A are as defined above for a compound of formula (I),

[0335] and their salts, especially pharmaceutically acceptable salts.

[0336] When B is a group B₇, f is advantageously one and g is two, or fis one and g is one and W₁₂, W₁₃, W₁₄, W₁₅ and W₁₆, together with thecarbon atom to which they are bonded, form one of the structures 1 to201 described below, optionally substituted by a halogen, a (C₁-C₇)alkylor a (C₁-C₇)alkoxy:

[0337] Consequently the compounds of formula (1) in which B is B₇ and g,f, W₁₂, W₁₃, W₁₄, W₁₅ and W₁₆ are as just defined, and their salts,especially pharmaceutically acceptable salts, are advantageous products.

[0338] The compounds of this subclass of formula (I) in whichsimultaneously:

[0339] B is a group B₇ selected from:

[0340] a) a 1-methanesulfonylspiro(indoline-3,4′-piperid-1′-yl)

[0341] b) a 1-benzyloxycarbonylspiro(indoline-3,4′-piperid-1′-yl)

[0342] c) a spiro(indoline-3,4′-piperid-1′-yl)

[0343] d) a 1-acetylspiro(indoline-3,4′-piperid-1′-yl)

[0344] e) a 1-propionylspiro(indoline-3,4′-piperid-1′-yl)

[0345] f) a 1-forrnylspiro(indoline-3,4′-piperid-1′-yl)

[0346] g) a 1-tert-butylcarbonylspiro(indoline-3,4′-piperid-1′-yl)

[0347] h) a 1-methylaminocarbonylspiro(indoline-3,4′-piperid-1′-yl)

[0348] i) a 1-ethoxycarbonylspiro(indoline-3,4′-piperid-1′-yl)

[0349] j) a 1-ethanesulfonylspiro(indoline-3,4′-piperid-1′-yl)

[0350] k) a 1-isopropanesulfonylspiro(indoline-3,4′-piperid-1′-yl)

[0351] l) a1′-methyl-1-methanesulfonylspiro(indoline-3,4′-piperidinio-1′) iodide

[0352] m) a 1-(2-aminoacetyl)spiro(indoline-3,4′-piperid-1′-yl)

[0353] n) a 1-methylspiro(indol-2-one-3,4′-piperid-1′-yl)

[0354] o) a 2-methylspiro(isoindol-1-one-3,4′-piperid-1′-yl)

[0355] p) a spiro(2-oxotetrahydroquinoline-4-4′-piperid-1′-yl)

[0356] q) a 1-methylspiro(2-oxotetrahydroquinoline-4,4′-piperid-1′-yl)

[0357] r) a spiro(2,3-dihydrobenzothiophene-3,4′-piperid-1′-yl)

[0358] s) a 5-fluorospiro(2,3-dihydrobenzofuran-3,4′-pipenid-1′-yl)

[0359] t) a spiro(2,3-dihydrobenzofuran-3,4′-piperid-1′-yl)

[0360] u) a spiro(2,3-dihydrobenzothu ophene-3,4′-piperid-1′-yl)1-oxide

[0361] v) aspiro(2,3-dihydrobenzothiophene-3,4′-piperid-1′-yl)1,1-dioxide

[0362] w) a 5-fluoro-1-methanesulfonylspiro(indoline-3,4′-piperid-1-yl)

[0363] x) a1-methanesulfonyl-5-methoxyspiro(indoline-3,4′-piperid-1′-yl)

[0364] y) a 1-methanesulfonyl-5-methylspiro(indoline-3,4′-piperid-1′-yl)

[0365] z) a 5-chloro-1-methanesulfonylspiro(indoline-3,4′-piperid-1′-yl)

[0366] aa) a7-fluoro-1-methanesulfonylspiro(indoline-3,4′-piperid-1′-yl)

[0367] ab) a 1-acetyl-5-fluorospiro(indoline-3,4′-piperid-1′-yl)

[0368] ac) a 1-acetyl-5-chlorospiro(indoline-3,4′-piperid-1′-yl)

[0369] ad) a 1-acetyl-5-methylspiro(indoline-3,4′-piperid-1′-yl)

[0370] ae) a 1-acetyl-6-fluorospiro(indoline-3,4′-piperid-1′-yl)

[0371] af) a 1-acetyl-4-fluorospiro(indoline-3,4′-piperid-1′-yl)

[0372] ag) a1-(N,N-dimethylcarbamoyl)spiro(indoline-3,4′-piperid-1′-yl);

[0373] R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0374] Ar₁ is a 3,4-dichlorophenyl;

[0375] Z═Z′; and

[0376] T and A are as defined above for (I),

[0377] and their salts, especially pharmaceutically acceptable salts,are particularly preferred.

[0378] When B is a group B₈, W₁₇ is advantageously a direct bond or amethylene group, preferably a direct bond, W₁₈ is an oxo, thioxo, imino,methylimino or ethylimino group, preferably an oxo or thioxo group, W₁₉is an oxy or thio group or a group NH, preferably an oxy group or agroup NH, and W₂₀ is an ethylene, cis-vinylene or trimethylene group.Consequently the compounds of formula (I) in which B is B₈ and W₁₇, W₁₈,W₁₉ and W₂₀ are as just defined, and their salts, especiallypharmaceutically acceptable salts, are advantageous products.

[0379] The compounds of this subclass of formula (I) in whichsimultaneously:

[0380] B is a group B₈ in which: W₁₇ is a direct bond, W₁₈ is an oxo orthioxo group, W₁₉ is an oxy group or a group NH and W₂₀ is an ethyleneor trimethylene group;

[0381] R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0382] Ar₁ is a 3,4-dichlorophenyl;

[0383] Z═Z′;and

[0384] T and A are as defined above for (I),

[0385] and their salts, especially pharmaceutically acceptable salts,are particularly preferred.

[0386] Another group of preferred compounds of the invention consists ofthe compounds of formula (I) in which R₁, R₂, Ar₁, T, A and Z are asdefined above for (I) and B is the group B₉.

[0387] The particularly preferred compounds of formula (I) are those inwhich simultaneously:

[0388] B is a group B₉ in which: X₂ is a group —COOR₆₈ or a group—C(═W₂₄)NR₇₀R₇, and W₂₁, W₂₂ and W₂₃, together with the nitrogen atom,form a 2-oxopiperidino group or a 2-oxoperhydropyrimidin-1-yl group;

[0389] R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0390] Ar₁ is a 3,4-dichlorophenyl;

[0391] Z═Z′; and

[0392] T and A are as defined above for (I),

[0393] and their salts, especially pharmaceutically acceptable salts.

[0394] Another group of preferred compounds of the invention consists ofthe compounds of formula (I) in which R₁, R₂, Ar₁, T, A and Z are asdefined above for (I) and B is the group B₁₀.

[0395] The particularly preferred compounds of formula (I) are those inwhich simultaneously:

[0396] B is a group B₁₀;

[0397] R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—;

[0398] Ar₁ is a 3,4-dichlorophenyl;

[0399] Z═Z′; and

[0400] T and A are as defined above for (I),

[0401] and their salts, especially pharmaceutically acceptable salts.

[0402] The more particularly preferred compounds of formula (I) arethose in which simultaneously:

[0403] B is a group B₁₀ in which J₆ is a group

[0404] in which:

[0405] W₂₅ is a piperid-1-yl and X₁ is a hydrogen, or W₂₅ is anazetidin-1-yl, a pyrrolidin-1-yl, a pirerid-1-yl, a morpholin-4-yl, athiomorpholin-4-yl or a perhydroazepin-1-yl and X₁ is a carbamoyl;

[0406] R₁ and R₂ together form a group —(CH₂)₃—;

[0407] Ar₁ is a 3,4-dichlorophenyl;

[0408] Z═Z′;

[0409] T is a group —CO—; and

[0410] A is a direct bond,

[0411] and their salts, especially pharmaceutically acceptable salts.

[0412] Another group of preferred compounds of the invention are thoseof the formula

[0413] in which:

[0414] Ar′₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)-alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different;

[0415] A′ is a direct bond or a group —CH₂—;

[0416] Z′ is as defined above; and

[0417] B_(a) is a group B_(1a) of the formula

[0418] in which J_(1a) is a group

[0419] in which:

[0420] x is zero;

[0421] Ar_(2a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; and

[0422] X_(1a) is a group selected from:

[0423] hydrogen;

[0424] (C₁-C₇)alkyl;

[0425] —(CH₂)_(m)—OR₄ in which m is two and R₄ is a hydrogen or a(C₁-C₇)alkyl;

[0426] —(CH₂)_(m)—OCOR₅ in which:

[0427] m is two and R₅ is a hydrogen; a (C₁-C₇)alkyl; a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; or a pyridyl; or m is zero or one and R₅ is a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; or a pyridyl;

[0428] —(CH₂)_(m)—OCONH(C₁-C₇)alkyl in which m is zero or two;

[0429] —O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; aformyl; or a (C₁-C₇)alkylcarbonyl;

[0430] —(CH₂)_(n)—SR₇ in which n is zero or one and R₇ is a hydrogen ora (C₁-C₇)alkyl;

[0431] —CH₂—S(O)_(j)—(C₁-C₇)alkyl in which j is one or two;

[0432] —NR₈R₉ in which R₈ and R₉, together with the nitrogen atom towhich they are bonded, form a piperazine heterocycle which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

[0433] —(CH₂)_(p)—NR₁₀R₁₁ in which p is two and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a(C₃-C₇)cycloalkylmethyl or a benzyl;

[0434] —NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a (C₁-C₇)alkyl and R₁₃is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;

[0435] —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₅is a (C₁-C₄)alkoxy;

[0436] —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is two, W₁ is an oxygen atomor a sulfur atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₆ is ahydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; a benzyl; a vinyl; apyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; and p is one,W₁ is a sulfur atom and R₁₄ and R₁₆ are as just defined, or W₁ is anoxygen atom, R₁₄ is as just defined and R₁₆ is a vinyl, a furyl, athienyl, a pyrrolyl or an imidazolyl;

[0437] —(CH₂)_(m)—NR₁₄COOR₁₇ in which m is two, R₁₄ is a hydrogen or a(C₁-C₇)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl;

[0438] —(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is two, R₁₄ is a hydrogen or a(C₁-C₇)alkyl and R₁₈ is a (C₁-C₇)alkyl; an amino which is free orsubstituted by one or two (C₁-C₇)alkyls; or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkylcarbonyloxy, acyano, a nitro and an amino which is free or substituted by one or two(C₁-C₇)alkyls, said substituents being identical or different;

[0439] —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is two, W₁ is an oxygenatom or a sulfur atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₉ andR₂₀ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₀ can also bea (C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a(C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; and m is zero or one, W₁ is a sulfur atom and R₁₄, R₁₉ andR₂₀ are as just defined, or W₁ is an oxygen atom, R₁₄ and R₁₉ are eachindependently a hydrogen or a (C₁-C₇)alkyl and R₂₀ is a (C₁-C₇)alkylsubstituted by a hydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a(C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted orsubstituted by one or two (C₁-C₇)alkyls; or R₁₉ and R₂₀, together withthe nitrogen atom to which they are bonded, form a piperazineheterocycle which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0440] —(CH₂)_(n)—COOR₂₁ in which n is one and R₂₁ is a hydrogen or a(C₁-C₇)alkyl; and n is zero and R₂₁ is a hydrogen;

[0441] —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is one, W₁ is an oxygen atomor a sulfur atom and R₁₉ and R₂₀ are each independently a hydrogen or a(C₁-C₇)alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; aphenyl; or a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, aphenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁-C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl; and nis zero, W₁ is a sulfur atom and R₁₉ and R₂₀ are as just defined, or W₁is an oxygen atom, R₁₉ is a hydrogen or a (C₁-C₇)alkyl and R₂₀ is a(C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, a phenyl, acarboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstitutedor substituted by one or two (C₁-C₇)alkyls; or R₁₉ and R₂₀, togetherwith the nitrogen atom to which they are bonded, form a piperazineheterocycle which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0442] —CO—NR₂₂NR₂₃R₂₄ in which R₂₂ is a hydrogen or a (C₁-C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

[0443] in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be aformyl or a (C₁-C₇)alkylcarbonyl; and

[0444] and their salts, especially pharmaceutically acceptable salts.

[0445] Among these compounds, those of the formula

[0446] in which:

[0447] B′_(a) is a group B′_(1a) of the formula

[0448] in which J′_(1a) is a group

[0449] in which:

[0450] x is zero;

[0451] Ar_(2a) is as defined for a compound of formula (Ia); and

[0452] X′_(1a) is a group selected from:

[0453] —O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; aformyl; or a (C₁-C₇)alkylcarbonyl;

[0454] —NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a (C₁-C₇)alkyl and R₁₃is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;

[0455] —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₅is a (C₁-C₄)alkoxy;

[0456] —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₆ is a vinyl, a furyl, athienyl, a pyrrolyl or an imidazolyl;

[0457] —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is zero, W₁ is an oxygenatom, R₁₄ is a hydrogen or a (C₁-C₇)alkyl, R₁₉ is a hydrogen or a(C₁-C₇)alkyl and R₂₀ is a (C₁-C₇)alkyl substituted by a hydroxyl, a(C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or acarbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls;

[0458] —CO—NR₂₂—NR₂₃R₂₄ in which R₂₂ is a hydrogen or a (C₁-C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

[0459] in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be aformyl or a (C₁-C₇)alkylcarbonyl; and

[0460] and their salts, especially pharmaceutically acceptable salts,are particularly preferred.

[0461] Among these compounds, those of the formula

[0462] in which:

[0463] X″_(1a) is a group selected from:

[0464] —O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; afornyl; or a (C₁-C₇)alkylcarbonyl, preferably a hydrogen or an acetyl;

[0465] —NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a (C₁-C₇)alkyl,preferably a hydrogen, and R₁₃ is a vinyl, a furyl, a thienyl, apyrrolyl or an imidazolyl, preferably a furyl or a thienyl;

[0466] —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl,preferably a hydrogen, and R₁₅ is a (C₁-C₄)alkoxy, preferably an ethoxy;and

[0467] in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl, preferably ahydrogen, and R₂₆ and R₂₇ are each independently a hydrogen or a(C₁-C₇)alkyl; R₂₇ can also be a formyl or a (C₁-C₇)alkylcarbonyl; R₂₆and R₂₇ are preferably a hydrogen; and

[0468] and their salts, especially pharmaceutically acceptable salts,are more particularly preferred.

[0469] Another group of preferred compounds of the invention are thoseof the formula

[0470] in which:

[0471] Ar′₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)-alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different;

[0472] A′ is a direct bond or a group —CH₂—;

[0473] Z′ is as defined above; and

[0474] B_(b) is a group B_(1b) of the formula

[0475] in which J_(1b) is a group

[0476] in which:

[0477] x is one;

[0478] Ar_(2a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; and

[0479] X_(1b) is a group selected from:

[0480] hydrogen;

[0481] (C₁-C₇)alkyl;

[0482] formyl;

[0483] (C₁-C₇)alkylcarbonyl;

[0484] —(CH₂)_(m)—OR₄;

[0485] —(CH₂)_(m)—OCOR₅;

[0486] —(CH₂)_(m)—OCONH—(C₁-C₇)alkyl;

[0487] —O—CH₂CH₂—OR₆;

[0488] —(CH₂)_(n)—SR₇;

[0489] —CH₂—S(O)_(j)—(C₁-C₇)alkyl;

[0490] —NR₈R₉;

[0491] —(CH₂)_(p)—NR₁₀R₁₁;

[0492] —NR₁₂COR₁₃;

[0493] —NR₁₄COCOR₁₅;

[0494] —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆;

[0495] —(CH₂)_(m)—NR₁₄COOR₁₇;

[0496] —(CH₂)_(m)—NR₁₄SO₂R₁₈;

[0497] —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀;

[0498] —(CH₂)_(n)—COOR₂₁;

[0499] —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀;

[0500] —CO—NR₂₂—NR₂₃R₂₄;

[0501] —CN;

[0502]  or X_(1b) forms a double bond between the carbon atom to whichit is bonded and the adjacent carbon atom of the piperidine ring,

[0503] in which groups:

[0504] m is zero, one or two;

[0505] n is zero or one;

[0506] p is one or two;

[0507] j is one or two;

[0508] W₁ is an oxygen atom or a sulfur atom;

[0509] R₄ is a hydrogen or a (C₁-C₇)alkyl;

[0510] R₅ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; or apyridyl;

[0511] R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl;

[0512] R₇ is a hydrogen or a (C₁-C₇)alkyl;

[0513] R₈ and R₉ are each independently a hydrogen or a (C₁-C₇)alkyl; R₉can also be a (C₃-C₇)cycloalkylmethyl, a benzyl or a phenyl;

[0514] or R₈ and R₉, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0515] R₁₀ and R₁₁ are each independently a hydrogen or a (C₁-C₇)alkyl;R₁₁ can also be a (C₃-C₇)cycloalkylmethyl or a benzyl;

[0516] R₁₂ is a hydrogen or a (C₁-C₇)alkyl;

[0517] R₁₃ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

[0518] or R₁₂ and R₁₃ together are a group —(CH₂)_(u)— in which u isthree or four;

[0519] R₁₄ is a hydrogen or a (C₁-C₇)alkyl;

[0520] R₁₅ is a (C₁-C₄)alkoxy;

[0521] R₁₆ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

[0522] R₁₇ is a (C₁-C₇)alkyl or a phenyl;

[0523] R₁₈ is a (C₁-C₇)alkyl; an amino which is free or substituted byone or two (C₁-C₇)alkyls; or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, a hydroxyl, a(C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a(C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, said substituents beingidentical or different;

[0524] R₁₉ and R₂₀ are each independently a hydrogen or a (C₁-C₇)alkyl;R₂₀ can also be a (C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; ahydroxyl; a (C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkylsubstituted by a hydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a(C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted orsubstituted by one or two (C₁-C₇)alkyls;

[0525] or R₁₉ and R₂₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0526] R₂₁ is a hydrogen or a (C₁-C₇)alkyl;

[0527] R₂₂ is a hydrogen or a (C₁-C₇)alkyl;

[0528] R₂₃ and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

[0529] R₂₅ is a hydrogen or a (C₁-C₇)alkyl; and

[0530] R₂₆ and R₂₇ are each independently a hydrogen or a (C₁-C₇)alkyl;R₂₇ can also be a formyl or a (C₁-C₇)alkylcarbonyl, with the provisothat:

[0531] when Ar′₁ is the 3,4-dichlorophenyl group and —A′—Z′ is the3-methoxybenzyl group, B_(b) is the group B_(1b) of the formula

[0532] in which x is one, Ar_(2a) is a phenyl group and X_(1b) is otherthan hydrogen, and their salts, especially pharmaceutically acceptablesalts.

[0533] Among these compounds, those of the formula

[0534] in which:

[0535] B′_(b) is agroup B′_(1b) of the formula

[0536] in which:

[0537] x is one;

[0538] Ar_(2a) is as defined for a compound of formula (Ib); and

[0539] X′_(1b) is as group s elected from:

[0540] —(C₁-C₇)alkyl;

[0541] —(CH₂)_(m)—OR₄ in which m is one or two and R₄ is a hydrogen or a(C₁-C₇)alkyl;

[0542] —(CH₂)_(m)—OCOR₅ in which:

[0543] m is zero and R₅ is a (C₃-C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; or a pyridyl; or

[0544] m is one or two and R₅ is a hydrogen; a (C₁-C₇)alkyl; a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; or a pyridyl;

[0545] —(CH₂)_(m)—OCONH—(C₁-C₇)alkyl in which m is zero, one or two;

[0546] —O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; aformyl; or a (C₁-C₇)alkylcarbonyl;

[0547] —(CH₂)_(n)—SR₇ in which n is zero or one and R₇ is a hydrogen ora (C₁-C₇)alkyl;

[0548] —CH₂—S(O)_(j)—(C₁-C₇)alkyl in which j is one or two;

[0549] —NR₈R₉ in which R₈ is a hydrogen or a (C₁-C₇)alkyl and R₉ is a(C₃-C₇)cycloalkylmethyl or a benzyl; or R₈ and R₉, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

[0550] —(CH₂)_(p)—NR₁₀R₁₁ in which p is one or two and R₁₀ and R₁₁ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a(C₃-C₇)cycloalkylmethyl or a benzyl;

[0551] —NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a (C₁-C₇)alkyl and R₁₃is a (C₃-C₇)-cycloalkyl which is unsubstituted or substituted by one ormore methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; or an imidazolyl; or R₁₂ and R₁₃ together are agroup —(CH₂)_(u)— in which u is three or four;

[0552] —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₅is a (C₁-C₄)alkoxy;

[0553] —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one or two, W₁ is anoxygen atom or a sulfur atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyl andR₁₆ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

[0554] —(CH₂)_(m)—NR₁₄COOR₁₇ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁-C₇)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl;

[0555] —(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁-C₇)alkyl and R₁₈ is a (C₁-C₇)alkyl; an amino which isfree or substituted by one or two (C₁-C₇)alkyls; or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a(C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, said substituents beingidentical or different;

[0556] —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is zero, one or two, W₁is an oxygen atom or a sulfur atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyland R₁₉ and R₂₀ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₀can also be a (C₃-C₇)-cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl;a (C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0557] —(CH₂)_(n)—COOR₂₁ in which n is one and R₂₁ is a hydrogen or a(C₁-C₇)alkyl;

[0558] —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is zero or one, W₁ is anoxygen atom or a sulfur atom and R₁₉ and R₂₀ are each independently ahydrogen or a (C₁-C₇)-alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; aphenyl; or a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, aphenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁-C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, formr aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

[0559] —CO—NR₂₂—NR₂₃R₂₄ in which R₂₂ is a hydrogen or a (C₁-C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

[0560] in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be aformyl or a (C₁-C₇)alkylcarbonyl; and

[0561] and their salts, especially pharmaceutically acceptable salts,are particularly preferred.

[0562] Among these compounds, those of the formula

[0563] in which:

[0564] X″_(1b) is a group selected from:

[0565] —(CH₂)_(p)—NR₁₀R₁₁ in which p is one and R₁₀ and R₁₁ are each ahydrogen;

[0566] —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₆ is a (C₁-C₇)alkyl,preferably an ethyl;

[0567] —(CH₂)_(m)—NR₁₄COOR₁₇ in which m is zero, R₁₄ is a hydrogen andR₁₇ is a (C₁-C₇)alkyl, preferably an ethyl; and

[0568] —(CH₂)_(m)—C(═W₁)NR₁₉R₂₀ in which n is zero, W₁ is an oxygen atomand R₁₉ and R₂₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl, preferably pyrrolidine,

[0569] and their salts, especially pharmaceutically acceptable salts,are more particularly preferred.

[0570] Another group of preferred compounds of the invention are thoseof the formula

[0571] in which:

[0572] Ar′₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)-alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different;

[0573] A′ is a direct bond or a group —CH₂—;

[0574] Z′ is as defined above; and

[0575] B_(c) is a group B_(1c) of the formula

[0576] in which J_(1c) is a group

[0577] in which:

[0578] x is zero or one;

[0579] Ar_(2a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; and

[0580] X_(1b) is as defined above for a compound of formula (I_(b)),

[0581] and their salts, especially pharmaceutically acceptable salts.

[0582] Among these compounds, those of the formula

[0583] in which:

[0584] B′_(c) is a group B′_(1c) of the formula

[0585] in which J′_(1c) is a group

[0586] in which:

[0587] x is zero or one;

[0588] Ar_(2a) is as defined for a compound of formula (Ic); and

[0589] X′_(1b) is a group selected from:

[0590] (C₁-C₇)alkyl;

[0591] —(CH₂)_(m)—OR₄ in which m is one or two and R₄ is a hydrogen or a(C₁-C₇)alkyl;

[0592] —(CH₂)_(m)—OCOR₅ in which m is zero and R₅ is a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;or a pyridyl; and m is one or two and R₅ is a hydrogen; a (C₁-C₇)alkyl;a (C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; or a pyridyl;

[0593] —(CH₂)_(m)—OCONH—(C₁-C₇)alkyl in which m is zero, one or two;

[0594] —O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; aformyl; or a (C₁-C₇)alkylcarbonyl;

[0595] —(CH₂)_(m)—SR₇ in which n is zero or one and R₇ is a hydrogen ora (C₁-C₇)alkyl;

[0596] —CH₂—S(O)_(j)—(C₁-C₇)alkyl in which j is one or two;

[0597] —NR₈R₉ in which R₈ is a hydrogen or a (C₁-C₇)alkyl and R₉ is a(C₃-C₇)cyclo-alkylmethyl or a benzyl; or R₈ and R₉, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

[0598] —(CH₂)_(p)—NR₁₀R₁₁ in which p is one or two, R₁₀ is a hydrogen ora (C₁-C₇)alkyl and R₁₁ is a hydrogen, a (C₁-C₇)alkyl, a(C₃-C₇)cycloalkylmethyl or a benzyl;

[0599] —NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a (C₁-C₇)alkyl and R₁₃is a (C₃-C₇)-cycloalkyl which is unsubstituted or substituted by one ormore methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; or an imidazolyl; or R₁₂ and R₁₃ together form agroup —(CH₂)_(u) in which u is three or four;

[0600] —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₅is a (C₁-C₄)alkoxy;

[0601] —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one or two, W₁ is anoxygen atom or a sulfur atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyl andR₁₆ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

[0602] —(CH₂)_(m)—NR₁₄COOR₁₇ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁-C₇)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl;

[0603] —(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁-C₇)alkyl and R₁₈ is a (C₁-C₇)alkyl; an amino which isfree or substituted by one or two (C₁-C₇)alkyls; or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a(C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, said substituents beingidentical or different;

[0604] —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is zero, one or two, W₁is an oxygen atom or a sulfur atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyland R₁₉ and R₂₀ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₀can also be a (C₃-C₇)-cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl;a (C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl;

[0605] —(CH₂)_(n)—COOR₂, in which n is one and R₂₁ is a hydrogen or a(C₁-C₇)alkyl;

[0606] —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is zero or one, W₁ is anoxygen atom or a sulfur atom and R₁₉ and R₂₀ are each independently ahydrogen or a (C₁-C₇)-alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; aphenyl; or a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, aphenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁-C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, forr aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

[0607] —CO—NR₂₂—NR₂₃R₂₄ in which R₂₂ is a hydrogen or a (C₁-C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

[0608] in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be aformyl or a (C₁-C₇)alkylcarbonyl; and

[0609] and their salts, especially pharmaceutically acceptable salts,are particularly preferred.

[0610] The following compounds:

[0611]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)-piperid-1-yl]propyl]piperidine;

[0612]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)-propyl]piperidine;

[0613]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-piperidinopiperid-1-yl)propyl]piperidine;

[0614]3-[3-[4-(acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

[0615]3-[3-[4-(2-aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

[0616]3-[3-(4-acetyl-4-benzylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichloro-phenyl)piperidine;

[0617]3-[3-[4-(acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

[0618]1-benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;

[0619]1-benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;

[0620]1-benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;

[0621]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(dimethylaminocarbonyl)-4-phenylpiperid-1-yl]propyl]perhydroazepine;

[0622]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenyl-piperid-1-yl]propyl]piperidine;

[0623]3-[3-[4-(2-acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

[0624]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidine;

[0625]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;

[0626]3-(3,4-dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;

[0627]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-spiro(indoline-3,4′-piperid-1′-yl)propyl]piperidine;

[0628]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4′-piperid-1-yl)]propyl]piperidine;

[0629]3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(2-thenoyl)piperidine;

[0630]3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(3-thenoyl)piperidine;

[0631]3-(3,4-dichlorophenyl)-1-(2-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;

[0632]3-(3,4-dichlorophenyl)-1-(3-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;

[0633]3-[3-[4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

[0634]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(ethoxalylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;

[0635]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-morpholinopiperid-1-yl)propyl]piperidine;

[0636]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methoxycarbonyl)spiro(indoline-3,4′-piperid-1′-yl)]propyl]piperidine;

[0637]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(N,N-dimethylcarbamoyl)spiro(indoline-3,4′-piperid-1′-yl)]propyl]piperidine;and

[0638]1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methanesulfonyl)spiro(indoline-3,4′-piperid-1′-yl)]propyl]piperidine,in the form of racemates or one of their (+) or (−) enantiomers,

[0639] and their salts, especially pharmaceutically acceptable salts,are very particularly preferred according to the present invention.

[0640] The invention further relates, where they exist, to the solvatesof the compounds of the invention and their salts, namely the compoundsof formulae (I), (I^(•)), (I^(••)), (I^(••)a), (Ia), (I′a), (I″a), (Ib),(I′b), (I″b), (Ic) and (I′c) and their salts.

[0641] The compounds according to the invention are obtained by knownmethods, particularly those described in patent applications EP-A-474561and EP-A-512 901.

[0642] One of the methods suitable for obtaining the compounds offormula (I) and their salts is described below.

[0643] According to this method:

[0644] 1) a compound of the formula

[0645] in which Ar₁, R₁ and R₂ are as defined for a compound of formula(I) and E is hydrogen or an O-protecting group, is treated:

[0646] either with a halogenated derivative of the formula

Hal—CH₂—A—Z   (III)

[0647] in which Hal is a halogen atom, preferably bromine, and A and Zare as defined for a compound of formula (I), when it is desired toprepare a compound of formula (I) in which T is a group —CH₂—;

[0648] or with a functional derivative of an acid of the formula

HO—CO—A—Z   (IIIa)

[0649] in which A and Z are as defined above, when it is desired toprepare a compound of formula (I) in which T is a group —CO—;

[0650] or with a chloroformate of the formula

Cl—COO—A—Z   (IIIb)

[0651] in which A and Z are as defined above, when it is desired toprepare a compound of formula (I) in which T is group —COO—;

[0652] or with an isocyanate of the formula

O═C═N—A—Z   (IIIc)

[0653] in which A and Z are as defined above, when it is desired toprepare a compound of formula (I) in which T is a group —CO—NR₃— inwhich R₃ is hydrogen;

[0654] or with a carbamoyl chloride of the formula

[0655] in which A and Z are as defined above and R′₃ is a (C₁-C₄)alkyl,when it is desired to prepare a compound of formula (I) in which T is—CONR₃— in which R₃ is a (C₁-C₄)alkyl;

[0656] or with a sulfonyl chloride of the formula

Cl—SO₂—Z   (IIIe)

[0657] in which Z is as defined above, when it is desired to prepare acompound of formula (I) in which —T—A— is a group —SO₂—, to give acompound of the formula

[0658] 2) the O-protecting group, if present, is removed from thecompound of formula (IV), by reaction with an acid or a base, to givethe alcohol of the formula

[0659]  3) the alcohol (V) is treated with a compound of the formula

G—SO₂—Cl   (VI)

[0660] in which G is a methyl, phenyl, tolyl or trifluoromethyl group,to give a compound of the formula

[0661]  4) the compound (VII) is reacted:

[0662] either with a cyclic secondary amine of the formula

[0663] in which J′₁ is:

[0664] * either a group

[0665] in which Ar₂ and x are as defined for (I) and X′₁ is either X₁ asdefined for (I), or a precursor of X₁, it being understood that when X′₁contains a hydroxyl group or an amino group, these groups can beprotected;

[0666] * either a group

[0667] in which Ar₂ is as defined for (I);

[0668] * or a group

[0669] in which Ar₂ is as defined for (I);

[0670] * or a group

[0671] in which Ar₂ is as defined for (I);

[0672] * or a group

[0673] in which Ar₂, Am₁ and r are as defined for (I);

[0674] or a group

[0675] in which Ar₂ and W₂ are as defined for (I);

[0676] or with a cyclic secondary amine of the formula

[0677] in which J₂ is as defined above for (I);

[0678] or with a cyclic secondary amine of the formula

[0679] in which J₃ is as defined above for (I);

[0680] or with a cyclic secondary amine of the formula

[0681] in which W₄ is as defined above for (I);

[0682] or with a cyclic secondary amine of the formula

[0683] in which W₆, W₇ and W₈ are as defined above for (I);

[0684] or with a cyclic secondary amine of the formula

[0685] in which J₄ is as defined above for (I);

[0686] or with a compound of the formula

[0687] in which f, g, W₁₂, W₁₃, W₁₄, W₁₅ and W₁₆ are as defined abovefor (I);

[0688] or with a cyclic secondary amine of the formula

[0689] in which W₁₇, W₁₈, W₁₉ and W₂₀ are as defined above for (I);

[0690] or with a cyclic secondary amine of the formula

[0691] in which J₅ is as defined above for (I);

[0692] or a cyclic secondary amine of the formula

[0693] in which J′₆ is a group

[0694] in which W₂₅ is as defined above for (I) and X′₁ is X₁ as definedfor (I), or a precursor of X₁, it being understood that when X′₁contains a hydroxyl group or an amino group, these groups can beprotected; and

[0695] 5) after deprotection of the hydroxyl groups or amino groups, ifappropriate, or conversion of X′₁ to X₁, if appropriate, the resultingproduct is optionally converted to one of its salts with a mineral ororganic acid.

[0696] In one variant of the method:

[0697] 1′) the nitrogen atom of the compound of formula (II) isprotected to give a compound of the formula

[0698] in which Ar₁, R₁ and R₂ are as defined for a compound of formula(I), E is hydrogen or an O-protecting group and Pr is an N-protectinggroup such as the trityl, tert-butoxycarbonyl or benzyloxycarbonylgroup;

[0699] 2′) the O-protecting group is eventually removed from thecompound of formula (XVII), by reaction with an acid or a base, to givethe alcohol of the formula

[0700] 3′) the alcohol (XVUI) is treated with a compound of formula (VI)as defined above to give a compound of the formula

[0701]  4′) the compound (XIX) is reacted with a compound of formula(VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh),(VIIIi) or (VIIIj) as defined above to give a compound of the formula

[0702] in which B is as defined for a compound of formula (I), it beingunderstood that when B contains a hydroxide group or an amino group,these groups can be protected;

[0703] 5′) the protecting group Pr is selectively removed from thecompound of formula (XX) to give the compound of the formula

[0704]  6′) the compound of formula (XXI) is treated with a compound offormula (III), (IlIa), (IIIb), (IIIc), (IIId) or (IIIe) as definedabove; and

[0705] 7′) after deprotection of the hydroxyl groups or amino groups, ifappropriate, the resulting product is optionally converted to one of itssalts with a mineral or organic acid.

[0706] More particularly, the compounds of formula (I^(•)) and theirsalts, especially pharmaceutically acceptable salts, are prepared by thevariant of the general method described above in which:

[0707] 1^(•)) a compound of the formula

[0708] in which G is a methyl, phenyl, tolyl or trifluoromethyl groupand Pr is an N-protecting group such as the trityl, tert-butoxycarbonylor benzyloxycarbonyl group, is reacted with a compound of the formula

[0709] in which J^(•) is as defined for a compound of formula (I^(•)),to give a compound of the formula

[0710] 2^(•)) the protecting group Pr is selectively removed from thecompound of formula (XX^(•)) to give the compound of the formula

[0711]  3^(•)) the compound of formula (XXI^(•)) is treated with afunctional derivative of an acid of the formula

HO—CO—Z^(•)  (III)

[0712] in which Z^(•) is as defined for a compound of formula (I^(•));and

[0713] 4^(•)) after deprotection, if appropriate, the resulting product(I^(•)) is optionally converted to one of its salts with a mineral ororganic acid.

[0714] During any one of the steps for the preparation of the compoundsof formula (I) or (I^(•)), and more particularly when using compounds offormula (VIIIa), (VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh),(VIIIi), (VIIIj) or (VIII^(•)) or intermediates of formula (II), (IV),(XX), (XXI), (XX^(•)) or (XXI^(•)), it may be necessary and/or desirableto protect the reactive or sensitive functional groups, such as theamine, hydroxyl or carboxyl groups, present on any one of the moleculesin question. This protection can be effected using the conventionalprotecting groups such as those described in Protective Groups inOrganic Chemistry, J. F. W. McOmie, published by Plenum Press, 1973, andin Protective Groups in Organic Synthesis, T. W. Greene and P. G. M.Wutts, published by John Wiley & Sons, 1991. The protecting groups canbe removed in an appropriate subsequent step by using the methods knownto those skilled in the art which do not affect the rest of the moleculein question.

[0715] Thus, when E is an O-protecting group, it is selected from theconventional O-protecting groups known to those skilled in the art, forexample tetrahydropyran-2-yl, benzoyl and a (C₁-C₄)alkylcarbonyl.

[0716] The O-protecting groups which may be used to obtain a compound offormula (I) in which X₁ contains a hydroxyl are the conventionalO-protecting groups known to those skilled in the art, as defined abovefor E.

[0717] The N-protecting groups which may be used to obtain a compound offormula (I) in which X₁ contains an amino group are the conventionalN-protecting groups known to those skilled in the art, for example thetrityl, methoxytrityl, tert-butoxycarbonyl or benzyloxycarbonyl group.

[0718] In step 1) of the method or in step 6′) of the variant, whenusing a halogenated derivative of formula (III), the reaction is carriedout in an inert solvent such as tetrahydrofuran, N,N-dimethylformamideor dimethyl sulfoxide, in the presence of a base such as potassiumtert-butylate, sodium hydride or lithium diisopropylamide, at atemperature between 0° C. and 80° C.

[0719] In step 1), in step 6′) or in step 3^(•)), the functionalderivative of the acid (IIIa) or (III^(•)) used is the acid itself orone of the functional derivatives which react with amines, for examplean anhydride, a mixed anhydride, the acid chloride or an activated estersuch as the paranitrophenyl ester.

[0720] When using the acid of formula (IIIa) or (III^(•)) itself, thereaction is carried out in the presence of a coupling agent used inpeptide chemistry, such as 1,3-dicyclohexylcarbodiimide orbenzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate,in the presence of a base such as triethylamine orN,N-diisopropylethylamine, in an inert solvent such as dichloromethaneor N,N-dimethylformamide, at a temperature between 0° C. and roomtemperature.

[0721] When using an acid chloride, the reaction is carried out in aninert solvent such as dichloromethane or benzene, in the presence of abase such as triethylamine or N-methylmorpholine, at a temperaturebetween −60° C. and room temperature.

[0722] When using a chloroformate of formula (IIIb), the reaction iscarried out in an inert solvent such as dichloromethane, at atemperature between 0° C. and room temperature, in the presence of abase such as triethylamine.

[0723] When using an isocyanate of formula (IIIc), the reaction iscarried out in an inert solvent such as dichloromethane or benzene, atroom temperature.

[0724] When using a carbamoyl chloride of formula (IIId), the reactionis carried out in a solvent such as toluene or 1,2-dichloroethane, at atemperature between 0° C. and 110° C., in the presence of a base such astriethylamine.

[0725] When using a sulfonyl chloride of formula (IIIe), the reaction iscarried out in an inert solvent such as dichloromethane, in the presenceof a base such as triethylamine, at a temperature between −20° C. androom temperature.

[0726] In step 2) of the method or in step 2′) of the variant, thecompound of formula (IV) or the compound of formula (XVII) thus obtainedis deprotected, if appropriate, by the methods known to those skilled inthe art. For example, when E is a tetrahydropyran-2-yl group, thedeprotection is effected by acid hydrolysis using hydrochloric acid in asolvent such as ether, methanol or a mixture of these solvents, or usingpyridinium p-toluenesulfonate in a solvent such as methanol, or elseusing an Amberlyst® resin in a solvent such as methanol, The reaction iscarried out at a temperature between room temperature and the refluxtemperature of the solvent. When E is a benzoyl group or a(C₁-C₄)alkylcarbonyl group, the deprotection is effected by hydrolysisin an alkaline medium using, for example, an alkali metal hydroxide suchas sodium hydroxide, potassium hydroxide or lithium hydroxide, in aninert solvent such as water, methanol, ethanol, dioxane or a mixture ofthese solvents, at a temperature between 0° C. and the refluxtemperature of the solvent.

[0727] In step 3) of the method or in step 3′) of the variant, thereaction of the alcohol of formula (V) or the alcohol of formula (XVIII)with a sulfonyl chloride of formula (VI) is carried out in the presenceof a base such as triethylamine, pyridine, N,N-diisopropylethylamine orN-methylmorpholine, in an inert solvent such as dichloromethane, benzeneor toluene, at a temperature between −20° C. and the reflux temperatureof the solvent.

[0728] In step 4) or in step 4′), the compound (VII) or the compound(XIX) thus obtained is reacted with a compound of formula (VIIIa),(VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi) or(VIlIj); in step 1^(•)), the compound (XIX^(•)) is reacted with acompound of formula (VIII^(•)). The reaction is carried out in an inertsolvent such as N,N-dimethylformamide, acetonitrile, methylene chloride,toluene, isopropanol or a mixture of these solvents, in the presence orabsence of a base. When using a base, it is selected from organic basessuch as triethylamine, N,N-diisopropylethylamine and N-methylmorpholine,or from alkali metal carbonates and bicarbonates such as potassiumcarbonate, sodium carbonate and sodium bicarbonate. In the absence of abase, the reaction is carried out using an excess of the compound offormula (VIIIa), (VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh),(VIIIi), (VIIIj) or (VIII^(•)) and optionally in the presence of analkali metal iodide such as potassium iodide or sodium iodide. Thereaction is carried out at a temperature between room temperature and100° C.

[0729] In step 5′) of the variant or in step 2^(•)), the compound offormula (XX) obtained or the compound of formula (XX^(•)) obtained isdeprotected by the methods known to those skilled in the art.

[0730] The compounds of formula (I) according to the invention arefinally obtained after deprotection of the hydroxyl groups or aminogroups, if appropriate, or conversion of X′₁ to X₁, if appropriate.

[0731] The compounds of formula (I) or (I^(•)) are isolated in the formof the free base or a salt by the conventional techniques.

[0732] Thus, when the compound of formula (I) or (I^(•)) is obtained inthe form of the free base, salification is effected by treatment withthe chosen acid in an organic solvent. Treatment of the free base,dissolved for example in an ether such as diethyl ether, in an alcoholsuch as propan-2-ol, in acetone, in dichloromethane or in ethyl acetate,with a solution of the chosen acid in the same solvent gives thecorresponding salt, which is isolated by the conventional techniques.

[0733] The hydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogen-phosphate, methanesulfonate, oxalate, maleate, fumarate,naphthalene-2-sulfonate and benzenesulfonate, for example, are preparedin this way.

[0734] When the reaction has ended, the compounds of formula (I) or(I^(•)) can be isolated in the form of one of their salts, for examplethe hydrochloride; in this case, if necessary, the free base can beprepared by neutralization of said salt with a mineral or organic basesuch as sodium hydroxide or triethylamine, or with an alkali metalcarbonate or bicarbonate such as sodium or potassium carbonate orbicarbonate.

[0735] The compounds of formula (II) are obtained by known methods,particularly those described in patent applications EP-A-0 428 434,EP-A-0 474 561 and EP-A-O 512 901.

[0736] In particular, a compound of formula (II) in which R₁ and R₂together form a group —(CH₂)₃— and E is a hydrogen can be preparedaccording to SCHEME 1 below:

[0737] In step 1, the reaction of a compound of formula (IX) with methylacrylate, in the presence of a base such as Triton® B or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), gives the compound of formula(X). The reaction is carried out in an inert solvent such as 1,4-dioxaneor tetrahydrofuran, at a temperature between 60° C. and the refluxtemperature of the solvent.

[0738] In step 2, the compound of formula (X) is hydrogenated in thepresence of a catalyst such as Raney® nickel to give the compound offormula (XI). The reaction is carried out in an inert solvent such as analkanol, preferably ethanol or 2-methoxyethanol, at a temperaturebetween room temperature and 60° C. and at a pressure betweenatmospheric pressure and 20 bar.

[0739] In step 3, the compound of formula (XI) is hydrolyzed in analkaline medium using, for example, an alkali metal hydroxide such assodium hydroxide or potassium hydroxide, in a solvent such as water,methanol or a mixture of these solvents, at a temperature between roomtemperature and the reflux temperature of the solvent.

[0740] The resulting compound of formula (XII) is reduced in step 4 togive the expected compound of formula (II). The reduction is effected bymeans of a reducing agent such as lithium aluminum hydride,diisobutylaluminum hydride or borane in THF, in an inert solvent such astetrahydroftiran, 1,2-dimethoxyethane or toluene, at a temperaturebetween room temperature and the reflux temperature of the solvent.

[0741] In particular, a compound of formula (I) in which R₁ and R₂together form a group —(CH₂)₄— and E is the O-protecting grouptetrahydropyran-2-yl (THP) can be prepared according to SCHEME 2 below:

[0742] In step 1′ of SCHEME 2, a compound of formula (IX) is treatedwith a strong base, such as sodium hydride, lithium diisopropylamide orpotassium tert-butylate, to give a carbanion, which is reacted withethyl 4-bromobutanoate to give the compound of formula (XIII).

[0743] The reaction is carried out in an inert solvent such as an ether(for example tetrahydrofuran or 1,2-dimethoxyethane), an amide (forexample N,N-dimethylformamide) or an aromatic hydrocarbon (for exampletoluene or xylene), at a temperature between −70° C. and +60° C.

[0744] In step 2′, the reaction of the compound of formula (XIII) with2-(3-bromo-propoxy)tetrahydropyran, in the presence of a strong basesuch as sodium hydride, lithium diisopropylamide or potassiumtert-butylate, under the operating conditions described in step 1′above, gives the compound of formula (XIV).

[0745] The nitrile derivative of formula (XIV) is reduced in step 3′ togive the primary amine of formula (XV). The reduction is effected bymeans of hydrogen, in the presence of a catalyst such as Raney® nickel,in an inert solvent such as an alkanol, for example methanol, by itselfor mixed with a saturated solution of ammonia in the same solvent, at atemperature between room temperature and 50° C.

[0746] In step 4′, the cyclized compound of formula (XVI) is obtained byrefluxing a solution of the compound of formula (XV) in an aromaticsolvent such as toluene or xylene.

[0747] In step 5′, the compound of formula (XVI) is reduced to give theexpected compound of formula (II). The reduction is effected by means ofa reducing agent such as lithium aluminum hydride, diisobutylaluminumhydride, sodium borohydride or borane in THF, in an inert solvent suchas tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene, at atemperature between room temperature and the reflux temperature of thesolvent.

[0748] The compounds of formula (III), (IIIa), (IIIb), (IIIc), (IIId),(IIIe) or (III¹⁰⁸ ) are known or are prepared by known methods.

[0749] The piperidines of formula (VIIIa) are known or are prepared byknown methods such as those described in EP-A-0 428 434, EP-A-0 474 561,EP-A-0512901 and EP-A-0 515240.

[0750] The piperidines of formula (VIIIa) can also be prepared bymethods well known to those skilled in the art, such as those describedin the following publications:

[0751] J. Heterocyclic Chem., 1986, 23, 73-75;

[0752] J. Chem. Soc., 1950, 1469;

[0753] J. Chem. Soc., 1945, 917;

[0754] J. Pharm. Sci., 1972, 61,1316-1317;

[0755] J. Org. Chem., 1957, 22, 1484-1489;

[0756] Chem. Ber., 1975, 108, 3475-3482.

[0757] The compounds of formula (VIIIa) are generally prepared in a formprotected on the piperidine nitrogen; the compounds of formula (VIIIa)themselves are obtained after a deprotection step.

[0758] Different methods of obtaining the compounds of formula (VIIIa),in which the different substituents are as defined for formula (I),unless stipulated otherwise, will be indicated below as examples.

[0759] For example, when Ar₂ is a pyrid-2-yl group, X′₁ is hydroxyl andx is zero in a piperidine of formula (VIIIa), 2-bromopyridine is reactedwith N-benzylpiperid-4-one in a solvent, in the presence ofbutyllithium, in order to prepareN-benzyl-4-hydroxy-4-(pyrid-2-yl)piperidine;4-hydroxy-4-(pyrid-2-yl)piperidine is then obtained by deprotection in abasic medium.

[0760] Furthermnore, a compound of formula (VIIIa) in which X′₁ is agroup —(CH₂)_(m)—OR₄ in which R₄ is hydrogen and m is one or two isprepared by reducing a compound of formula (VIIIa) in which X′₁ is amethoxycarbonyl or, respectively, a methoxycarbonylmethyl by the methoddescribed in Chem. Ber., 1975, 108, 3475-3482.

[0761] A compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—OR₄ in which R₄ is a (C₁-C₇)alkyl can also be prepared byalkylating a compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—OH by the methods known to those skilled in the art.

[0762] A compound of formula (VIIIa) in which X′hd 1 is a group—O—CH₂—CH₂—OR₆ in which R₆ is hydrogen can also be prepared by reactinga compound of formula (VIIIa) in which X′₁ is a benzoyloxy- withethylene glycol in the presence of an acid such as sulfuric acid.

[0763] The compounds of formula (VIIIa) in which X′₁ is a group—O—CH₂CH₂—OR₆ in which R₆ is a (C₁-C₇)alkyl are prepared by an identicalreaction using a 2-(C₁ -C₇)alkoxyethanol.

[0764] The compounds of formula (VIIIa) in which X′hd 1 is a group—O—CH₂CH₂—OR₆ in which R₆ is a formyl are prepared by reacting forrnicacid with a compound of formula (VIIIa) in which X′₁ is a group—O—CH₂CH₂—OH. The compounds of formula (VIIIa) in which X′₁ is a group—O—CH₂CH₂—OR₆ in which R₆ is a (C₁-C₇)-alkylcarbonyl are prepared byreaction with a C₂-C₈ acid chloride in the presence of a base such astriethylamine.

[0765] The compounds of formula (VIIIa) in which X′₁ is a group—(CH₂)_(n)—SR₇ or a group —CH₂—S(O)_(j)—(C₁-C₇)alkyl are known or areprepared by known methods such as those described in WO 95/12577.

[0766] The compounds of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—OCOR₅ (R₅ other than hydrogen) are prepared by reacting anacid chloride R₅COCl (R₅ other than hydrogen) with a compound of formula(VIIIa) in which X′₁ is a group —(CH₂)_(m)—OH, in the presence of a basesuch as triethylamine.

[0767] The compounds of formula (VHIa) in which X′₁ is a group—(CH₂)_(m)—OCOR₅ in which R₅ is hydrogen are prepared by reacting formicacid with a compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—OH.

[0768] The compounds of formula (VIIIa) in which X′₁ is a group(C₁-C₇)alkyl-NHCOO—(CH₂)_(m)— are obtained by reacting a carbamoylchloride, (C₁-C₇)alkyl-NHCOCl, with the compounds of formula (VIIIa) inwhich X′₁ is a group —(CH₂)_(m)—OH. The same compounds are prepared byreacting an isocyanate, (C₁-C₇)alkyl-N═C═O, with the compounds offormula (VIIIa) in which X′₁ is a group —(CH₂)_(m)—OH.

[0769] The compounds of formula (VIIIa) in which X′₁ is a hydroxyl andwhich carry a protecting group on the piperidine nitrogen can undergo aRitter reaction with acetonitrile in order to prepare the compounds offormula (VIIIa) in which X′₁ is an acetamido. The compounds of formula(VIIIa) in which X′₁ is a group —NR₈R₉ in which R₈ and R₉ are eachhydrogen are then prepared by hydrolysis in an acid medium.

[0770] A compound of formula (VIIIa) in which X′₁ is a group —NR₈R₉ inwhich R₈ and R₉ are each hydrogen can also be prepared by hydrolyzing ina strong acid medium, for example hydrochloric acid, a compound offormula (VIIIa) in which X′₁ is an isocyanato group.

[0771] A compound of formula (VIIIa) in which X′₁ is a group —NR₈R₉ inwhich R₈ is hydrogen and R₉ is a (C₁-C₇)alkyl, or a(C₃-C₇)cycloalkylmethyl or a benzyl, can be prepared by reducing acompound of formula (VIIIa) in which X′₁ is a group —NR₁₂COR₁₃ in whichR₁₂ is hydrogen and R₁₃ is a hydrogen or a (C₁-C₆)alkyl or,respectively, a (C₃-C₇)cycloalkyl or a phenyl. The reaction is carriedout by means of a reducing agent such as lithium aluminum hydride, in asolvent such as tetra-hydrofuran, at the reflux temperature of thesolvent.

[0772] The compounds of formula (VIIIa) in which X′₁ is a group —NR₈R₉in which R₈ is a (C₁-C₇)alkyl can be prepared by an identical reactionfrom the compounds of formula (VIIIa) in which X′₁ is a group —NR₁₂COR₁₃in which R₁₂ is a (C₁-C₇)alkyl.

[0773] A compound of formula (VIIIa) in which X′₁ is a group —NR₈R₉ inwhich R₈ and R₉, together with the nitrogen atom to which they arebonded, form a hetero-cycle is prepared by applying or adaptingBruylants' reaction (Bull. Soc. Chim. Belges, 1924, 33 467, andTetrahedron Letters, 1988, 29 (52), 6827 - 6830).

[0774] A compound of formula (VIIIa) in which X′₁ is a group—CH₂—NR₁₀R₁₁ in which R₁₀ and R₁₁ are each hydrogen is prepared byreducing a compound of formula (VIIIa) in which X′₁ is a cyano. Thisreduction is effected by the methods well known to those skilled in theart.

[0775] A compound of formula (VIIIa) in which X′₁ is a group—CH₂—CH₂—NR₁OR₁₁ in which R₁₀ and R₁₁ are each a hydrogen is preparedfrom a compound of formula (VIIIa) in which X′₁ is a group —CH₂—CH₂—OHby applying or adapting the method described in J. Med. Chem., 1989, 32,391-396.

[0776] The compounds of formula (VIIIa) in which X′₁ is a group—(CH₂)_(p)—NR₁OR₁₁ in which R₁₀ is a hydrogen or a (C₁-C₇)alkyl and R₁₁is a (C₁-C₇)alkyl, a (C₃-C₇)-cycloalkylmethyl or a benzyl can beprepared by reducing a compound of formula (VIIIa) in which X′₁ is agroup —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which R₁₄ is a hydrogen or a(C₁-C₇)alkyl, R₁₆ is a hydrogen, a (C₁-C₆)alkyl, a (C₃-C₇)cycloalkyl ora phenyl and W₁ is an oxygen atom.

[0777] The compounds of formula (VIIIa) in which X′₁ is a group—NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a (C₁-C₇)alkyl and R₁₃ ishydrogen or respectively a (C₁-C₇)alkyl, an optionally substituted(C₃-C₇)cycloalkyl, a phenyl, a benzyl, a vinyl, a pyridyl, a furyl, athienyl, a pyrrolyl or an imidazolyl are obtained by reacting formicacid in acetic anhydride or, respectively, an appropriate acid chlorideR₁₃COCl, in the presence of a base such as triethylamine, with acompound of formula (VIIIa) in which X′₁ is a group —NHR₁₂. Inparticular, a compound of formula (VIIIa) in which X′₁ is a group—NR₁₂COR₁₃ in which R₁₃ is an ethyl radical can be prepared byhydrogenating, in the presence of a catalyst such as palladium oncharcoal, a compound of formula (VIIIa) in which X′₁ is an acryloylaminoor acryloyl-N-(C₁-C₇)alkylamino group.

[0778] A compound of formula (VIIIa) in which X′₁ is a group —NR₁₂COR₁₃in which R₁₂ and R₁₃ together are a group —(CH₂)₃— or —(CH₂)₄— isprepared by applying or adapting the method described in J. Med. Chem.,1985, 28, 46-50.

[0779] A compound of formula (VIIIa) in which X′₁ is a group—NR₁₄COCOR₁₅ in which R₁₅ is a (C₁-C₄)alkoxy is prepared by reacting acompound of the formula Cl—COCOR₁₅ with a compound of formula (VIIIa) inwhich X′₁ is a group —NHR₁₄.

[0780] The compounds of formula (VIIIa) in which X′₁ is a group—(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which W₁ is an oxygen atom, p is 1 or 2, R₁₄is a hydrogen or a (C₁-C₇)alkyl and R₁₆ is a hydrogen or respectively a(C₁-C₇)alkyl, a phenyl, a benzyl, a pyridyl, an optionally substituted(C₃-C₇)cycloalkyl, a vinyl, a furyl, a thienyl, a pyrrolyl or animidazolyl are obtained by reacting formic acid in acetic anhydride or,respectively, an appropriate acid chloride R₁₆COCl, in the presence of abase such as triethylamine, with a compound of formula (VIIIa) in whichX′₁ is a group —CH₂—NHR₁₄ or —CH₂—CH₂—NHR₁₄.

[0781] A compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which W₁ is a sulfur atom is obtained from acorresponding compound of formula (VIIIa) which is protected on thepiperidine nitrogen and in which W₁ is an oxygen atom by reaction withphosphorus pentasulfide or with Lawesson's reagent,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disphosphetane-2,4-disulfide,followed by deprotection of the piperidine nitrogen.

[0782] A compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—NR₁₄COOR₁₇ is prepared by reacting a chloroformate of theformula ClCOOR₁₇ with a compound of formula (VIIIa) in which X′₁ is agroup (CH₂)_(m)NHR₁₄, in the presence of a base such as triethylamine.

[0783] It is also possible to prepare a compound of formula (VIIIa) inwhich X′₁ is a group (CH₂)_(m)—NR₁₄COOR₁₇ in which m=0 and R₁₄ ishydrogen by reacting a compound R₁₇OH with a compound of formula (VIIIa)in which X′₁ is an isocyanato group (—N═C═O).

[0784] A compound of formula (VIIIa) in which X′₁ is an isocyanato groupis prepared from a compound of formula (VIIIa) in which X′₁ is acarboxyl group by the method described in Organic Synthesis, 51, 48-52.

[0785] A compound of formula (VIIIa) in which X′₁ is a group(CH₂)_(m)—NR₁₄SO₂R₁₈ is prepared by reacting a sulfonyl chlorideClSO₂R₁₈ with a compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—NHR₁₄, in the presence of a base such as triethylamine.

[0786] Likewise, the compounds of formula (VIIIa) in which X′₁ is agroup —(CH₂)_(m)—NR₁₄CONR₁₉R₂₀ in which R₁₉ is a hydrogen and R₂₀ is a(C₁-C₇)alkyl are prepared by reaction with an isocyanate of the formulaR₂₀N═C═O in which R₂₀ is a (C₁-C₇)alkyl.

[0787] The compounds of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—N—R₁₄CONR₁₉R₂₀ in which R₁₉ is a (C₁-C₇)alkyl are prepared byreaction with a carbamoyl chloride of the formula ClCONR₁₉R₂₀.

[0788] A compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—NR₁₄CONR₁₉R₂₀ can also be obtained by reacting a compoundHNR₁₉R₂₀ with a compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—NR₁₄COOR₁₇ in which R₁₇ is a phenyl.

[0789] A compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—NR₁₄CONR₁₉R₂₀ in which m=0 and R₁₄ is hydrogen can also beprepared by reacting a compound NHR₁₉R₂₀ with a compound of formula(VIIIa) in which X′₁ is an isocyanato group.

[0790] A compound of formula (VIIIa) in which X′₁ is a group—(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which W₁ is a sulfur atom is prepared byreacting a compound of formula (VIIIa), protected on the piperidinenitrogen, in which X′₁ is a group —(CH₂)_(m)—NR₁₄CONR₁₉R₂₀ withphosphorus pentasulfide or with Lawesson's reagent.

[0791] A compound of fonnula (VIIIa) in which X′₁ is a group —CONR₁₉R₂₀is prepared by reacting a compound of formula (VIIIa) in which X′₁ is acarboxyl with a compound of formula HNR₁₉R₂₀ by the methods well knownto those skilled in the art.

[0792] Likewise, the compounds of formula (VIIIa) in which X′₁ is agroup —CH₂—CONR₁₉R₂₀ are prepared by reacting a compound of formula(VIIIa) in which X′₁ is a group —CH₂—COOR₂ in which R₂₁ is hydrogen witha compound HNR₁₉R₂₀.

[0793] A compound of formula (VIIIa) in which X′₁ is a group(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which W₁ is a sulfur atom is prepared, by theabove-mentioned methods, from a compound of corresponding formula(VIIIa) in which W₁ is an oxygen atom.

[0794] A compound of formula (VIIIa) in which X′₁ is a carboxyl can beprepared by hydrolyzing a compound of formula (VIIIa) in which X′₁ is acyano by the methods known to those skilled in the art.

[0795] A compound of formula (VIIIa) in which X′₁ is a carboxymethyl canbe prepared by the method described in Chem. Ber., 1975, 108, 3475-3482.

[0796] A compound of formula (VIIIa) in which X′₁ is a(C₁-C₇)alkoxycarbonyl or a (C₁-C₇)alkoxycarbonylmethyl can be preparedfrom a compound of formula (VIIIa) in which X′₁ is a carboxyl or,respectively, a carboxymethyl by means of an esterification reaction bythe methods well known to those skilled in the art.

[0797] In particular, a compound of formula (VIIIa) in which Ar₂ is anoptionally substituted phenyl radical, x is one and X′₁ is a(C₁-C₇)alkoxycarbonyl is prepared by reacting a protected4-(C₁-C₇)alkoxycarbonylpiperidine with an optionally substituted benzylhalide in the presence of a base such as sodium hydride, potassiumtert-butylate or sodium diisopropylamide, in a solvent such astetra-hydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, at atemperature between −78° C. and room temperature. The expected compoundof formula (VIIIa) is obtained after a deprotection step.

[0798] A compound of formula (VIIIa) in which X′₁ is a group—CO—NR₂₂—NR₂₃R₂₄ is prepared by reacting a hydrazine HNR₂₂—NR₂₃R₂₄ witha compound of formula (VIIIa) in which X′₁ is a chloroformyl.

[0799] A compound of formula (VIIIa) in which X′₁ is a group

[0800] in which R₂₆ and R₂₇ are each independently a hydrogen or a(C₁-C₇)alkyl is prepared by reacting a compound of formula (VIIIa) inwhich X′¹ is a group

[0801] in which Hal is a halogen atom, preferably bromine, with athiourea in which one of the amino groups is free or substituted by oneor two (C₁-C₇)alkyls.

[0802] A compound of formula (VIIIa) in which X′₁ is a group

[0803] in which R₂₇ is a formyl or respectively a (C₁-C₇)alkylcarbonylis prepared by reacting formic acid in acetic anhydride or,respectively, an acid chloride (C₁-C₇)alkyl-COCl, in the presence of abase such as tniethylamine, with the above compound of formula (VIIIa),protected on the piperidine nitrogen, in which R₂₇ is hydrogen. Theexpected compound is obtained after a deprotection step.

[0804] The compound of formula (VIIIa) in which X′₁ is a group

[0805] in which Hal is a bromine atom is obtained by the bromination, bythe conventional methods, of a compound of formula (VIIIa) in which X′₁is a group —CO—CH₂—R₂₅.

[0806] A compound of formula (VIIIa) in which X′₁ is a group

[0807] can be prepared by reacting a protected compound of formula(VIIIa) in which X′₁ is a carbazoyl group (—CONH—NH₂) with cyanogenbromide by the method described in J. Org. Chem., 1961, 26, 88-95. Thecompound of formula (VIIIa) in which X′₁ is a carbazoyl group isobtained by reacting hydrazine with a compound of formula (VIIIa) inwhich X′₁ is a chloroformyl, which is itself obtained by reactingthionyl chloride with a compound of formula (VIIIa) in which X′₁ is acarboxyl.

[0808] The piperazines of formula (VIIIb) are known or are prepared byknown methods such as those described in EP-A-0 428 434.

[0809] The piperidines of formula (VIIIc) are known or are prepared byknown methods such as those described in WO 94/10146.

[0810] The piperidines of formula (VIIId) are known or are prepared byknown methods such as those described in EP-A-0 625 509.

[0811] The piperidines of formula (VIIIe) are known or are prepared byknown methods such as those described in EP-A-0 630 887.

[0812] The piperidines of formula (VIIIf) are known or are prepared byknown methods such as those described in WO 94/26735.

[0813] The compounds of formula (VIIIg) are known or are prepared byknown methods such as those described in WO 94/29309.

[0814] The piperidines of formula (VIIIh) are known or are prepared byknown methods such as those described in WO 95/05377.

[0815] The piperidines of formula (VIIIi) are known or are prepared byknown methods such as those described in WO 95/12577.

[0816] The piperidines of formula (VIIIj) are known or are prepared byknown methods.

[0817] In particular, the piperidines of formula (VIIIj) in which J′₆ isa group

[0818] in which X′₁ is other than hydrogen and W₂₅ is a (C₁-C₇)alkyl ora (C₃-C₇)cycloalkyl are prepared by the procedures described above forthe preparation of the piperidines of formula (VIIIa).

[0819] A piperidine of formula (VIIIj) in which J′₆ is a group

[0820] in which W₂₅ is a group —NR₇₉R₈₀ and X′₁ is a cyano is preparedby means of a Strecker reaction between a 1-benzylpiperid-4-one and acompound of the formula NHR₇₉R₈₀ in the presence of sodium cyanide. Thecompound of expected formula (VIIIj) is obtained after a deprotectionstep. Hydrolysis of the cyano group in a strong medium by the methodsknown to those skilled in the art gives the corresponding piperidines offormula (VIIIj) in which X′₁ is a carboxyl. The latter compounds can beused to obtain the corresponding piperidines of formula (VIIIj) in whichX′₁ is a (C₁-C₇)alkoxycarbonyl or a group —CONR₁₉R₂₀ by the methodsknown to those skilled in the art, for example by means ofesterification or, respectively, by the methods of peptide coupling.

[0821] The piperidines of formula (VIII^(•)) are also known or can beprepared by known methods. In particular, when J^(•) is a group of thestructure

[0822] the piperidine of formula (VIII^(•)) is prepared by one of themethods described above for the compounds of formula (VIIIa) in whichX′₁ is a group —CONR₁₉R₂₀, especially by reacting a carboxylic acid ofthe formula

[0823] with an amine of the formula NHR₁₉R₂₀.

[0824] When J^(•) is a group of the structure

[0825] the piperidine of formula (VIII^(•)) is prepared by methodsdescribed in WO 94/29309.

[0826] The enantiomers of the compounds according to the invention, ofthe formula

[0827] in which:

[0828] “*” denotes that the carbon atom carrying this label has thedetermined (+) or (−) absolute configuration; and

[0829] R₁, R₂, Ar₁, T, A, Z and B are as defined for the compounds offormula (I), and their salts with mineral or organic acids, are novelcompounds which form part of the invention.

[0830] The enantiomers of formula (I*) can be isolated by resolution ofthe racemic mixtures of the compounds of formula (I). It is preferable,however, to resolve the racemic mixtures at the stage of an intermediatewhich can be used to prepare a compound of formula (I), as described inpatent applications EP-A-0 474 561, EP-A-0 512 901, EP-A-0 591 040 andEP-A-0 612 716.

[0831] The compounds of formula (I) above also include those in whichone or more hydrogen, carbon or iodine atoms have been replaced by theirradioactive isotope, for example tritium, carbon 14 or iodine 125. Suchlabeled compounds are useful in research, metabolic or pharmacokineticstudies and in biochemical assays as receptor ligands.

[0832] The affinity of the compounds of formula (I) for the tachykininreceptors was evaluated in vitro by means of several biochemical assaysusing radioligands:

[0833] 1^(•)) The binding of [¹²⁵I]BH-SP (substance P labeled withiodine 125 using Bolton-Hunter's reagent) to the NK₁ receptors of ratcortex, guinea-pig ileum and human lymphoblastic cells.

[0834] 2^(•)) The binding [¹²⁵I]His-NK_(A) to the NK₂ receptors of ratbladder or the binding [¹²⁵I]NPγ to the NK₂ receptors of guinea-pigileum.

[0835] 3^(•)) The binding [¹²⁵I]His[MePhe⁷]NK_(B) to the NK₃ receptorsof rat cerebral cortex, guinea-pig cerebral cortex and gerbil cerebralcortex and to the human NK₃ cloned receptors expressed by CHO cells(Buell et al., FEBS Letters, 1992, 299, 90-95).

[0836] The assays were performed according to X. Emonds-Alt et al. (Eur.J. Pharmacol., 1993, 250, 403-413).

[0837] The compounds according to the invention strongly inhibit thebinding of [¹²⁵I]His[MePHe⁷]NK_(B) to the NK₃ receptors of guinea-pigand gerbil cerebral cortex and to the human NK₃ cloned receptors: theinhibition constant Ki is generally less than 5.10⁻⁹ M. For the samecompounds, it was found that the inhibition constant (Ki) for the NK₃receptors of rat cerebral cortex is generally greater than 10⁻⁹ M andthat the inhibition constant (Ki) for the NK₂ receptor of rat duodenumand the NK₁ receptors of rat cortex is generally greater than or equalto 10⁻⁷ M.

[0838] The compounds according to the present invention were alsoevaluated in vivo on two animal models.

[0839] In the gerbil, a rotational behavior is induced by theintrastriatal administration of the specific NK₃ receptor agonistsenktide; it was found that a unilateral administration of senktide togerbil striatum leads to strong contralateral rotations which areinhibited by the compounds according to the invention, administeredeither intraperitoneally or orally.

[0840] This result shows that the compounds according to the inventionpass through the blood-brain barrier and that they are capable ofblocking the characteristic action of the NK₃ receptors in the centralnervous system. They may thus be used for the treatment of anyNK_(B)-dependent pathological condition of the central nervous system,such as psychiatric diseases, or any pathological condition mediated bythe NK₃ receptor in the central nervous system, such as psychosomaticdiseases.

[0841] In the guinea-pig, an intravenous or intracerebroventricularinjection of senktide induces hypertension which is suppressed by theoral or intravenous administration of the compounds according to theinvention.

[0842] This result shows that the compounds according to the inventionact on the cardiovascular system and that they are capable of blockingthe characteristic action of the NK₃ receptors in said system,especially hypertension (Nakayama et al., Brain Res., 1992, 595,339-342; Takano and Kamiya, Asia Pacific J. Pharmacol., 1991, 6,341-346; Saigo et al., Neuroscience Letters, 1993, 159, 187-190).

[0843] In the guinea-pig, the inhalation of substance P, for example,induces bronchial hyperreactivity to acetylcholine and hypersensitivityto histamine, for example in the plasmic extravasation. An NK₃antagonist blocks these two characteristic processes of respiratorypathological conditions like asthma.

[0844] In these tests, the compounds according to the invention areactive at doses varying from 0.1 mg to 30 mg per kg, administeredorally, intravenously or intraperitoneally.

[0845] The compounds of the present invention are generally administeredin dosage units. Said dosage units are preferably formulated intopharmaceutical compositions in which the active principle is mixed witha pharmaceutical excipient.

[0846] According to another of its aspects, the present inventionrelates to pharmaceutical compositions containing, as the activeprinciple, a compound of formula (I) or one of its pharmaceuticallyacceptable salts which has a very high affinity for the human NK₃receptor, said affinity being characterized by an inhibition constant Kigenerally of less than 5.10⁻⁹ M in ligand binding studies.

[0847] The compounds of formula (I) and their pharmaceuticallyacceptable salts can be used in daily doses of 0.01 to 100 mg perkilogram of body weight of the mammal to be treated, preferably in dailydoses of 0.1 to 50 mg/kg. In humans the dose can preferably vary from0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg, dependingon the age of the subject to be treated or the type of treatment:prophylactic or curative.

[0848] Examples of diseases which can be treated using the compounds andtheir pharmaceutically acceptable salts are diseases associated with adysfunction of the dopaminergic systems, such as schizophrenia andParkinson's disease, diseases associated with a dysfunction of thenoradrenergic and serotoninergic systems, such as anxiety, vigilancedisorders and humor disorders, all forms of epileptic disease,particularly grand mal, dementia, neurodegenerative diseases, peripheraldiseases in which the central nervous system and/or the peripheralnervous system participate via neurokinin B acting as a neurotransmitteror neuromodulator, such as pain, migraine and acute or chronicinflammation, cardiovascular disorders, particularly hypertension,cardiac insufficiency and rhythm disorders, respiratory disorders(asthma, rhinitis, cough, bronchitis, allergy, hypersensitivity),disorders of the gastrointestinal system, such as esophageal ulcer,colitis, stress-related disorders, irritable bowel syndrome (IBS) andacidic secretion, emesis/nausea (following chemotherapy, postoperative,due to travel sickness or due to vestibular disorders), disorders of theurinary system (incontinence, nervous bladder), diseases of the immunesystem (rheumatoid arthritis) and, more generally, any neurokininB-dependent pathological condition.

[0849] In the pharmaceutical compositions of the present invention fororal, sublingual, inhalational, subcutaneous, intramuscular,intravenous, transdermal, local or rectal administration, the activeprinciples can be administered to animals and humans in unit forms ofadministration, mixed with conventional pharmaceutical carriers. Theappropriate unit forms of administration include forms for oraladministration, such as tablets, gelatin capsules, powders, granules andsolutions or suspensions to be taken orally, forms for sublingual andbuccal administration, forms for subcutaneous, intramuscular,intravenous, intranasal or intraocular administration and forms forrectal administration.

[0850] When a solid composition in the form of tablets is prepared, themain active principle is mixed with a pharmaceutical vehicle such assilica, gelatin, starch, lactose, magnesium stearate, talcum, gum arabicor the like. The tablets can be coated with sucrose various polymers orother appropriate substances or else they can be treated so as to have asustained or delayed activity and so as to release a predeterminedamount of active principle continuously.

[0851] A preparation in the form of gelatin capsules is obtained bymixing the active principle with a diluent, such as a glycol or aglycerol ester, and introducing the mixture obtained into soft or hardgelatin capsules.

[0852] A preparation in the form of a syrup or elixir can contain theactive principle together with a sweetener, which is preferablycalorie-free, methylparaben and propylparaben as antiseptics, aflavoring and an appropriate color.

[0853] The water-dispersible granules or powders can contain the activeprinciple mixed with dispersants or wetting agents or with suspendingagents such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

[0854] Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

[0855] Parenteral, intranasal or intraocular administration is effectedusing aqueous suspensions, isotonic saline solutions or injectablesolutions which contain pharmacologically compatible dispersants and/orwetting agents, for example propylene glycol or butylene glycol.

[0856] Administration by inhalation is effected using an aerosol whichalso contains, for example, sorbitan trioleate or oleic acid, as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propellant gas; it is also possibleto use a system containing the active principle, by itself or inassociation with an excipient, in powder form.

[0857] The active principle can also be presented in the form of acomplex with a cyclodextrin, for example α-, β- or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

[0858] The active principle can also be formulated as microcapsules,with one or more carriers or additives if appropriate.

[0859] In each dosage unit, the active principle of formula (I) ispresent in the amounts commensurate with the daily doses envisaged. Ingeneral, each dosage unit is appropriately adjusted according to thedosage and the intended type of administration, for example tablets,gelatin capsules and the like, sachets, ampoules, syrups and the like,or drops, so that said dosage unit contains from 0.5 to 1000 mg ofactive principle, preferably from 2.5 to 250 mg, for administration oneto four times a day.

[0860] The above-mentioned compositions can also contain other activeproducts which are useful for the desired therapeutics, such as, forexample, bronchodilators, antitussives or antihistamines.

[0861] By virtue of their very high affinity for the human NK₃ receptorand their high selectivity, the compounds according to the invention maybe used in radio-labeled form as laboratory reagents.

[0862] For example, they make it possible to characterize, identify andlocate the human NK₃ receptor in tissue sections or the NK₃ receptor inthe whole animal by autoradiography.

[0863] The compounds according to the invention also make it possible tosort or screen molecules as a function of their affinity for the humanNK₃ receptor. This is carried out by means of a reaction in which theradiolabeled ligand forming the subject of the present invention isdisplaced from its human NK₃ receptor.

[0864] The following abbreviations are used in the Preparations and inthe

EXAMPLES

[0865] Me, OMe: methyl, methoxy

[0866] Et, OEt: ethyl, ethoxy

[0867] EtOH: ethanol

[0868] MeOH: methanol

[0869] Ether: diethyl ether

[0870] Iso ether: diusopropyl ether

[0871] DMF: dimethylformamide

[0872] DMSO: dimethyl sulfoxide

[0873] DCM: dichloromethane

[0874] THF: tetrahydrofuran

[0875] AcOEt: ethyl acetate

[0876] K₂CO₃: potassium carbonate

[0877] Na₂CO₃: sodium carbonate

[0878] KHCO₃: potassium hydrogencarbonate

[0879] NaHCO₃: sodium hydrogencarbonate

[0880] NaCl: sodium chloride

[0881] Na₂SO₄: sodium sulfate

[0882] MgSO₄: magnesium sulfate

[0883] NaOH: sodium hydroxide

[0884] AcOH: acetic acid

[0885] H₂SO₄: sulfuric acid

[0886] HCl: hydrochloric acid

[0887] Ethereal hydrogen chloride: saturated solution of hydrochloricacid in ether

[0888] BOP: benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate

[0889] KCN: potassium cyanide

[0890] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0891] NH₄Cl: ammonium chloride

[0892] M.p.: melting point

[0893] B.p.: boiling point

[0894] RT: room temperature

[0895] Silica H: silica gel 60H marketed by Merck (DARMSTADT)

[0896] NMR: nuclear magnetic resonance

[0897] δ: chemical shift

[0898] s: singlet

[0899] bs: broad singlet

[0900] rs: resolved singlet

[0901] d: doublet

[0902] t: triplet

[0903] qd: quadruplet

[0904] sept: septuplet

[0905] mt: multiplet

[0906] us: unresolved signals

PREPARATION 1.1 4-(Pyrrolidin-1-ylcarbonyl)piperidine hydrochloride

[0907] A) 1-tert-Butoxycarbonyl-4-carboxypiperidine

[0908] 8.6 g of triethylamine and 20 ml of water are added to a solutionof 10 g of isonipecotic acid in 100 ml of dioxane and the mixture isheated to 60° C. 20.25 g of di-tert-butyl carbonate are then addeddropwise and the mixture is stirred for 1 hour at 60° C. and refluxedfor 30 minutes. It is concentrated under vacuum, the residue is taken upwith water and acidified to pH 3 by the addition of 2 N HCl solution andthe precipitate formed is filtered off to give 17 g of the expectedproduct.

[0909] B) 1-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)piperidine

[0910] 1.32 g of triethylamine, 2.5 g of the compound obtained in theprevious step and then 5.31 g of BOP are added to a solution of 0.77 gof pyrrolidine in 20 ml of DCM and the mixture is stirred for 1 hour atRT. It is concentrated under vacuum, the residue is taken up with waterand extracted with ether, the organic phase is washed with water, with10% NaOH solution, with water, with a buffer solution of pH 2, withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 2.25 g of the expectedproduct.

[0911] C) 4-(Pyrrolidin-1-ylcarbonyl)piperidine hydrochloride p 20 ml of6 N HCl solution are added to a solution of 2.25 g of the compoundobtained in the previous step in 40 ml of MeOH and the mixture isstirred for 1 hour at RT. The solvent is concentrated under vacuum, theresidue is taken up with acetone and the solvent is evaporated off undervacuum to give 1.75 g of the expected product after crystallization fromAcOEt.

PREPARATION 1.2 4-Carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride

[0912] A) 1-Benzyl-4-cyano-4-(piperid-1-yl)piperidine

[0913] A solution of 5.3 g of sodium cyanide in 20 ml of water is addeddropwise at RT to a solution of 18.9 g of 1-benzylpiperid-4-one and12.16 g of piperidine hydrochloride in 25 ml of MeOH and 25 ml of waterand the mixture is stirred for 48 hours at RT. The precipitate formed isfiltered off, washed with water and dried under vacuum to give 27 g ofthe expected product.

[0914] B) 1-Benzyl-4-carbamoyl-4-(piperid-1-yl)piperidine

[0915] 10 g of the compound obtained in the previous step are added to50 ml of 95% sulfuric acid and the mixture is heated at 100° C. for 45minutes. After cooling to RT, the reaction mixture is poured onto 100 gof ice, 250 ml of DCM are added, with cooling, the organic phase isdried over MgSO₄ and the solvent is evaporated off under vacuum. Thesolid product obtained is recrystallized from 300 ml of anacetonitrile/toluene mixture (65/35; v/v) to give 9.7 g of the expectedproduct, m.p.=150-160° C.

[0916] C) 4-Carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride

[0917] 10 g of ammonium formate and 2.5 g of 5% palladium on charcoalare added to a solution of 9.7 g of the compound obtained in theprevious step in 200 ml of MeOH and the mixture is stirred for 2 hoursat RT. It is filtered on Célite® and the filtrate is evaporated undervacuum. The residue is dissolved in 2 N HCl solution, rendered alkalineto pH 13 by the addition of 40% NaOH solution and extracted withchloroform, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum. The product obtained is dissolved in anMeOH/DCM mixture, acidified to pH 1 by the addition of ethereal hydrogenchloride and evaporated under vacuum to give 5 g of the expectedproduct, m.p.=185° C.

PREPARATION 1.3

[0918]4-(Acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride

[0919] A) 1-Benzyl-4-hydroxy-4-phenylpiperidine

[0920] This compound is prepared by reacting phenyllithium with1-benzylpiperid-4-one by the method described in EP-A-474 561.

[0921] B) 4-Acetamido-1-benzyl-4-phenylpiperidine

[0922] This compound is prepared by reacting acetonitrile with thecompound obtained in the previous step by the method described inEP-A-474 561.

[0923] C) 4-Amino-1-benzyl-4-phenylpiperidine dihydrochloride

[0924] A mixture of 50 g of the compound obtained in the previous step,90 ml of concentrated HCl solution and 210 ml of water is refluxed for48 hours. The reaction mixture is concentrated under vacuum, the residueis taken up with an EtOH/toluene mixture and the solvents are evaporatedoff under vacuum. The residue is dissolved in 100 ml of hot MeOH, 500 mlof acetone are added and the mixture is stirred, with cooling in an icebath. The crystals formed are filtered off, washed with acetone and thenwith ether and dried to give 48.9 g of the expected product.

[0925] D) 1-Benzyl-4-(formylamino)-4-phenylpiperidine

[0926] 110 ml of acetic anhydride are added dropwise to a solution of48.9 g of the compound obtained in the previous step and 25 g of sodiumformate in 340 ml of formic acid and the reaction mixture is then leftto stand overnight at RT, with stirring. It is concentrated undervacuum, the residue is taken up with water, rendered alkaline by theaddition of concentrated NaOH solution and extracted with DCM, theorganic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 38.8 g of the expected product aftercrystallization from an iso ether/pentane mixture, m.p.=140° C.

[0927] E) 1-Benzyl-4-(methylamino)-4-phenylpiperidine

[0928] A solution of 38.8 g of the compound obtained in the previousstep in 400 ml of THF is added slowly to a suspension of 12.5 g oflithium aluminum hydride in 100 ml of THF and the reaction mixture isrefluxed for 3 hours. After cooling, a solution of 5 ml of concentratedNaOH in 45 ml of water is added, the inorganic salts are filtered offand the filtrate is concentrated under vacuum to give 38 g of theexpected product.

[0929] F) 4-(Acryloyl-N-methylamino)-1-benzyl-4-phenylpiperidine

[0930] A solution of 1.5 g of the compound obtained in the previous stepand 1.5 ml of triethylamine in 40 ml of DCM is cooled to 0-5° C., 0.5 mlof acryloyl chloride is added dropwise and the reaction mixture isstirred, the temperature being allowed to rise to RT. It is poured intowater, the resulting mixture is decanted, the organic phase is washedwith water and with 2 N NaOH solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 1.3 g of the expectedproduct after crystallization from an ether/pentane mixture.

[0931] G) 4-(Acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride

[0932] A solution of 1.3 g of the compound obtained in the previous stepin 30 ml of 1,2-dichloroethane is cooled to 0° C., 0.5 ml of1-chloroethyl chloroformate is added dropwise and the reaction mixtureis then refluxed for 2 hours. It is concentrated under vacuum and theresidue is taken up with 15 ml of MeOH, refluxed for 30 minutes andconcentrated under vacuum to give 0.65 g of the expected product aftercrystallization from AcOEt.

PREPARATION 1.4

[0933] 4-(2-Aminothiazol-4-yl)-4-phenylpiperidine p-toluenesulfonatemonohydrate

[0934] A) 4-(2-Bromoacetyl)-4-phenylpiperidine hydrobromide

[0935] 8 g of bromine are added rapidly at RT to a suspension of 11.98 gof 4-acetyl-4-phenylpiperidine hydrochloride in 200 ml of DCM and thereaction mixture is left to stand overnight at RT, with stirring. It isdiluted by the addition of 200 ml of ether and the precipitate formed isfiltered off and washed with ether to give 17.88 g of the expectedproduct after drying under vacuum.

[0936] B) 4-(2-Aminothiazol-4-yl)-4-phenylpiperidine p-toluenesulfonatemonohydrate

[0937] A mixture of 7.26 g of the compound obtained in the previousstep, 1.52 g of thiourea and 150 ml of EtOH is refluxed for 3 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upwith water and rendered alkaline to pH 13 by the addition of 10% NaOHsolution and the precipitate formed is filtered off and washed withwater and then with ether to give 4.46 g of the expected product in theform of the free base after recrystallization from EtOH. 1 g of the baseis dissolved in acetone and 0.73 g of p-toluenesulfonic acidmono-hydrate is added to give 1.5 g of the expected product in the formof crystals, m.p.=220-222° C.

PREPARATION 1.5 4-Acetyl-4-benzylpiperidine hydrochloride

[0938] A) 4-Cyanopiperidine

[0939] 25 g of isonipecotamide (or piperidine-4-carboxamide) are addedin small portions to 70 ml of POCl₃ and the reaction mixture is refluxedfor 4 hours. It is concentrated under vacuum, the residue is taken upwith ice, rendered alkaline to pH 13 by the addition of concentratedNaOH solution and extracted with DCM and then 4 times with ether, thecombined organic phases are dried over MgSO₄ and the solvents areevaporated off under vacuum. The oil obtained is distilled under reducedpressure to give 6.4 g of the expected product, b.p.=108-110° C. under18 mm of mercury.

[0940] B) 4-Cyano-1,4-dibenzylpiperidine

[0941] A solution of 15 g of the compound obtained in the previous stepin 250 ml of THF is cooled to −50° C., 190 ml of a 1.5 M solution oflithium diisopropylamide in cyclohexane are added dropwise and themixture is stirred for 30 minutes at −50° C. 34 ml of benzyl bromide arethen added and the reaction mixture is stirred, the temperature beingallowed to rise to RT. After 3 hours at RT, it is poured into a mixtureof ice and concentrated HCl, ether is added and the precipitate formedis filtered off and washed with water. The precipitate is taken up withwater, rendered alkaline to pH 13 by the addition of concentrated NaOHsolution and extracted with ether, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum to give 31.7 g of theexpected product after crystallization from pentane, m.p.=92° C.

[0942] C) 4-Acetyl-1,4-dibenzylpiperidine hydrochloride

[0943] 55 ml of a 1.6 M solution of methyllithium in ether are added toa solution of 20 g of the compound obtained in the previous step in 400ml of ether and the reaction mixture is stirred for 3 hours at RT. It ispoured into iced water, the resulting mixture is decanted, the organicphase is dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is taken up with 400 ml of water, 40 ml ofconcentrated HCl are added and the mixture is refluxed for 2 hours.After one night at RT, the crystalline product formed is filtered offand washed with a small amount of acetone and then with ether to give17.6 g of the expected product after drying, m.p.=246° C.

[0944] D) 4-Acetyl-4-benzylpiperidine hydrochloride

[0945] A mixture of 3 g of the compound obtained in the previous step,0.3 g of 10% palladium on charcoal, 50 ml of EtOH and 10 ml of water ishydrogenated at RT and at atmospheric pressure. The catalyst is filteredoff and the filtrate is evaporated under vacuum to give 1.8 g of theexpected product after crystallization from acetone, m.p.=195° C.

PREPARATION 1.6 4-(Acetylamino)-4-benzylpiperidine p-toluenesulfonate

[0946] A) 1,4-Dibenzyl-4-carboxypiperidine

[0947] 6 g of the compound obtained in step B of PREPARATION 1.5 areadded to a solution of 25 ml of water, 25 ml of concentrated H₂SO₄ and25 ml of AcOH and the reaction mixture is heated at 140° C. for 5 hours.After cooling, it is poured onto ice, the pH is brought to 6.5 by theaddition of concentrated NaOH solution and the mixture is stirred untilcrystallization takes place. The crystalline product is filtered off andwashed with water. The product is taken up with MeOH, filtered off andwashed with ether to give 3 g of the expected product, m.p.=262° C.

[0948] B) 1,4-Dibenzyl-4-isocyanatopiperidine

[0949] A mixture of 2 g of the compound obtained in the previous stepand 1.6 g of phosphorus pentachloride in 40 ml of chloroform is heatedat 60° C. for 1 hour. The reaction mixture is concentrated under vacuum,the residue is taken up with 40 ml of acetone, a solution of 2 g ofsodium azide in 5 ml of water is added and the mixture is stirred for 30minutes at RT. It is concentrated under vacuum at RT, the residue istaken up with ether, the organic phase is washed with saturated Na₂CO₃solution and with water and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with 40 ml oftoluene and refluxed for 1 hour. It is concentrated under vacuum to give2 g of the expected product in the form of an oil.

[0950] C) 4-Amino-1,4-dibenzylpiperidine dihydrochloride

[0951] A mixture of 1 g of the compound obtained in the previous stepand 20 ml of 8 N HCl is refluxed for 45 minutes. It is concentratedunder vacuum and the residue is dissolved in the minimum amount of EtOHand poured into ether. The precipitate formed is filtered off, washedwith ether and dried to give 1 g of the expected product, m.p.=199° C.(dec.).

[0952] D) 4-Acetylamino-1,4-dibenzylpiperidine

[0953] 0.23 ml of acetyl chloride is added to a solution of 1 g of thecompound obtained in the previous step and 1.4 ml of triethylamine in 20ml of DCM and the reaction mixture is stirred for 15 minutes at RT. Itis washed with water and with saturated Na₂SO₄ solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 0.75 g ofthe expected product after crystallization from iso ether, m.p.=134° C.

[0954] E) 4-(Acetylamino)-4-benzylpiperidine p-toluenesulfonate

[0955] A mixture of 0.746 g of the compound obtained in the previousstep, 0.44 g of p-toluenesulfonic acid monohydrate, 0.2 g of 10%palladium on charcoal and 30 ml of EtOH is stirred for 48 hours under ahydrogen atmosphere. The catalyst is filtered off and the filtrate isconcentrated under vacuum to give 0.88 g of the expected product in theform of a foam.

PREPARATION 1.7 4-Benzyl-4-cyanopiperidine

[0956] A) 4-Cyano-1-tritylpiperidine

[0957] A solution of 6.4 g of the compound obtained in step A ofPREPARATION 1.5 in 60 ml of DCM is cooled to 5° C., 10.8 ml oftriethylamine are added, 18 g of trityl chloride are then added slowlyand the reaction mixture is stirred, the temperature being allowed torise to RT. It is washed with water and with a buffer solution of pH 2,the organic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 19 g of the expected product after crystallizationfrom iso ether, m.p.=206° C.

[0958] B) 4-Benzyl-4-cyano-1-tritylpiperidine

[0959] A solution of 5 g of the compound obtained in the previous stepin 50 ml of THF is cooled to −50° C., 9.5 ml of a 1.5 M solution oflithium diusopropylamide in cyclohexane are added dropwise and themixture is stirred for 30 minutes at −50° C. 1.7 ml of benzyl bromideare then added and the reaction mixture is stirred for 30 minutes. It ispoured into a mixture of ice and a buffer solution of pH 2 and extractedwith ether, the extract is washed with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum to give 5.69 gof the expected product after crystallization from iso ether.

[0960] C) 4-Benzyl-4-cyanopiperidine

[0961] A mixture of 5.7 g of the compound obtained in the previous step,25 ml of formic acid and 25 ml of water is heated at 60° C. for 1 hour.After cooling to RT, the insoluble material is filtered off and washedwith water and the filtrate is evaporated under vacuum. The residue istaken up with water, rendered alkaline to pH 13 by the addition ofconcentrated NaOH solution and extracted with ether, the organic phaseis dried over MgSO₄ and the solvent is evaporated off under vacuum togive 2.5 g of the expected product.

PREPARATION 1.8 4-Benzyl-4-(ethoxycarbonylamino)piperidinep-toluenesulfonate

[0962] A) 1,4-Dibenzyl-4-(ethoxycarbonylamino)piperidinep-toluenesulfonate

[0963] A mixture of 1 g of the compound obtained in step B ofPREPARATION 1.6 and 20 ml of EtOH is refluxed for 24 hours. It isconcentrated under vacuum, the oil obtained is dissolved in 5 ml ofacetone, 0.55 g of para-toluenesulfonic acid monohydrate is added andether is then added until crystallization takes place. The crystalsformed are filtered off, washed with ether and dried to give 1.38 g ofthe expected product, m.p.=154° C.

[0964] B) 4-Benzyl-4-(ethoxycarbonylamino)piperidine p-toluenesulfonate

[0965] A mixture of 1.3 g of the compound obtained in the previous step,0.15 g of 10% palladium on charcoal and 20 ml of EtOH is stirred for 24hours under a hydrogen atmosphere. The catalyst is filtered off and thefiltrate is concentrated under vacuum to give 1 g of the expectedproduct in the form of a foam.

PREPARATION 1.9 4-Benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidinep-toluenesulfonate

[0966] A) 1,4-Dibenzyl-4-(pyrrolidin-1-ylcarbonyl)piperidine

[0967] 0.5 g of pyrrolidine and then 3.8 g of BOP are added to asolution of 2.2 g of the compound obtained in step A of PREPARATION 1.6and 2.5 ml of triethylamine in 50 ml of DCM and the reaction mixture isstirred for 1 hour at RT. It is concentrated under vacuum, the residueis extracted with AcOEt, the organic phase is washed with water, with 1N NaOH solution, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica using DCM and then a DCM/MeOH mixture(90/10; v/v) as the eluent. The product obtained is taken up with anether/1 N HCl mixture, the resulting mixture is decanted, the aqueousphase is rendered alkaline to pH 13 by the addition of 1 N NaOH andextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 0.64 g of the expectedproduct after crystallization from iso ether, m.p.=129° C.

[0968] B) 4-B enzyl-4-pyrrolidin-1-ylcarbonyl)piperidinep-toluenesulfonate

[0969] A mixture of 0.64 g of the compound obtained in the previousstep, 0.33 g of p-toluenesulfonic acid monohydrate, 0.1 g of 10%palladium on charcoal and 10 ml of EtOH is hydrogenated at RT and atatmospheric pressure. The catalyst is filtered off and the filtrate isevaporated under vacuum to give 0.75 g of the expected product in theform of a foam.

PREPARATION 1.10 4-(Acetyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate

[0970] A) 4-(Acetyl-N-methylamino)-1-benzyl-4-phenylpiperidine

[0971] A solution of 30 g of the compound obtained in step E ofPREPARATION 1.3 and 16.5 ml of triethylamine in 300 ml of DCM is cooledto 0-5° C., 8 ml of acetyl chloride are added dropwise and the reactionmixture is stirred for 30 minutes at RT. It is washed twice with waterand with 2 N NaOH solution, the organic phase is dried over MgSO₄ andthe solvent is evaporated off under vacuum to give 31.6 g of theexpected product after crystallization from an iso ether/pentanemixture, m.p.=104° C.

[0972] B) 4-(Acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate

[0973] A mixture of 5 g of the compound obtained in the previous step,2.9 g of p-toluenesulfonic acid monohydrate, 0.5 g of 10% palladium oncharcoal and 80 ml of EtOH is hydrogenated for 3 hours at 25° C. and atatmospheric pressure. The catalyst is filtered off and the filtrate isconcentrated under vacuum to give 5.7 g of the expected product aftercrystallization from acetone, m.p.=165° C.

PREPARATION 1.1 1 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidinehemihydrate

[0974] A) 1-tert-Butoxycarbonyl-4-carboxy-4-phenylpiperidine

[0975] 30 ml of water and 32.9 g of K₂CO₃ are added to a mixture of 30 gof 4-carboxy-4-phenylpiperidine p-toluenesulfonate and 300 ml ofdioxane, the resulting mixture is then heated to 60° C. and 18.2 g ofdi-tert-butyl dicarbonate are added dropwise. The reaction mixture issubsequently heated for 2 hours at 60° C. and then for 30 minutes underreflux. After cooling to RT, it is concentrated under vacuum, theresidue is extracted with DCM, the organic phase is washed with a buffersolution of pH 2, acidified to pH 4 by the addition of 2 N HCl, washedwith a buffer solution of pH 2, with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 23.7 g of the expected product.

[0976] B)1-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)-4-phenylpiperidine

[0977] 9.29 g of triethylamine and then 3.27 g of pyrrolidine are addedto a solution of 14 g of the compound obtained in the previous step in200 ml of DCM. The mixture is cooled in an ice bath, 22.4 g of BOP areadded and the reaction mixture is stirred, the temperature being allowedto rise to RT. It is concentrated under vacuum, the residue is extractedwith DCM, the organic phase is washed with water, three times with 10%NaOH solution, with water, three times with a buffer solution of pH 2,with water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 16.4 g of the expectedproduct.

[0978] C) 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine hemihydrate

[0979] Concentrated HCl solution is added to a solution of 16.4 g of thecompound obtained in the previous step in 200 ml of MeOH until the pH is1, and the reaction mixture is stirred for 5 hours at RT. It isconcentrated under vacuum, the residue is taken up with acetone and thesolvent is evaporated off under vacuum to give a white solid, which isrecrystallized from propan-2-ol. The product obtained is taken up with10% NaOH solution and extracted with DCM, the organic phase is washedwith 10% NaOH solution and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 7 g of theexpected product after crystallization from ether, m.p.=126° C.

PREPARATION 1.12 4-(N,N-Dimethylaminocarbonyl)-4-phenylpiperidine

[0980] A)1-tert-Butoxycarbonyl-4-(N,N-dimethylaminocarbonyl)-4-phenylpiperidine

[0981] 8.1 g of triethylamine and then 4.9 g of dimethylaminehydrochloride are added to a solution of 6.11 g of the compound obtainedin step A of PREPARATION 1.11 in 20 ml of DCM and 20 ml of DMF. Themixture is cooled in an ice bath, 9.73 g of BOP are added and theresulting mixture is stirred for 3 hours, the temperature being allowedto rise to RT. It is concentrated under vacuum, the residue is extractedwith ether, the organic phase is washed with water, with a buffersolution of pH 2, with 10% NaOH solution, with water and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 6.45 g of the expected product.

[0982] B) 4-(N,N-Dimethylaminocarbonyl)-4-phenylpiperldine

[0983] Concentrated HCl solution is added to a solution of 6.4 g of thecompound obtained in the previous step in 80 ml of MeOH until the pH is1, and the mixture is stirred for 4 hours at RT. It is concentratedunder vacuum, the residue is extracted with DCM, the organic phase iswashed three times with 10% NaOH solution and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 3.2 g of the expected product after crystallization fromether, m.p.=95° C.

PREPARATION 1.13 4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride

[0984] A) 1-Benzyl-4-hydroxy-4-phenylpiperidine

[0985] This compound is prepared by reacting phenyllithium with1-benzylpiperid-4-one by the method described in EP-A-474 561.

[0986] B) 4-(Benzoyloxy)-1-benzyl-4-phenylpiperidine

[0987] A solution of 2.67 g of the compound prepared in the previousstep and 2.5 ml of triethylamine in 30 ml of DCM is cooled to 0-5° C.,1.22 ml of benzoyl chloride are added and the reaction mixture isstirred for 1 hour, the temperature being allowed to rise to RT. It isconcentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with water and with 1 N NaOH solution and driedover MgSO₄ and the solvent is evaporated off under vacuum to give 2.4 gof the expected product after crystallization from pentane.

[0988] C) 1-Benzyl-4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride

[0989] A mixture of 2.3 g of the compound obtained in the previous step,7 ml of H₂SO₄ and 60 ml of ethylene glycol is heated at 60° C. for 5hours. The reaction mixture is poured onto ice, rendered alkaline by theaddition of concentrated NH₄OH solution and extracted with DCM, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. Theproduct obtained is dissolved in DCM and acidified to pH 1 by theaddition of ethereal hydrogen chloride and the precipitate formed isfiltered off to give 1 g of the expected product.

[0990] D) 4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride

[0991] A mixture of 3.3 g of the compound obtained in the previous step,0.4 g of 10% palladium on charcoal and 100 ml of EtOH is hydrogenated atRT and at atmospheric pressure. The catalyst is filtered off on Célite®and the filtrate is concentrated under vacuum to give 2.2 g of theexpected product, m.p.=168-172° C.

PREPARATION 1.14 4-Amino-4-phenylpiperidine dibenzenesulfonate

[0992] 26.95 g of the compound obtained in steo C of PREPARATION 1.3 aredissolved in 50 ml of water, rendered alkaline to pH 12 by the additionof concentrated NaOH solution and extracted with DCM, the organic phaseis washed with saturated NaCl solution and dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The oil obtained is taken upwith 300 ml of EtOH, 25 g of benzenesulfonic acid and 2.2 g of 5%palladium on charcoal are added and the mixture is then hydrogenated at40° C. and at atmospheric pressure. The catalyst is filtered off onCélite and washed with MeOH and the filtrate is concentrated undervacuum. The residue is taken up with acetone and the precipitate -formedis filtered off to give 29.7 g of the expected product, m.p.=276-278° C.

PREPARATION 1.15 4-(2-Amino- 1,3,4-oxadiazol-5-yl)-4-phenylpiperidinep-toluenesulfonate

[0993] A) 1-(Benzyloxycarbonyl)-4-carboxy-4-phenylpiperidine

[0994] A mixture of 37.7 g of 4-carboxy-4-phenylpiperidinep-toluenesulfonate, 53.3 g of 30% aqueous NaOH solution and 250 ml ofwater is cooled to 5° C. A solution of 18 g of benzyl chloroformate in60 ml of acetone is added rapidly at 5° C. and the reaction mixture isstirred overnight, the temperature being allowed to rise to RT. It iswashed twice with ether and. after decantation, the aqueous phase isacidified to pH 1 by the addition of concentrated HCl and then 2 N HCl.The precipitate formed is filtered off, dried, taken up with ether andfiltered off again to give 30.6 g of the expected product, m.p.=142-144°C.

[0995] B) 1-(Benzyloxycarbonyl)-4-(chloroformyl)-4-phenylpiperidine

[0996] A mixture of 17.1 g of the compound obtained in the previousstep, 24 g of thionyl chloride and 150 ml of 1,2-dichloroethane isrefluxed for 1 hour. It is concentrated under vacuum, the residue istaken up with chloroform and the solvent is evaporated off under vacuum.The residue is taken up with an ether/pentane mixture and the solventsare evaporated off again under vacuum to give 20 g of the expectedproduct in the form of a gum, which is used as such.

[0997] C) 1-(Benzyloxycarbonyl)-4-carbazoyl-4-phenylpiperidine

[0998] A solution of 16 g of hydrazine monohydrate in 40 ml of EtOH iscooled to −50° C., a solution of 11.44 g of the compound obtained in theprevious step in 20 ml of 1,2-dimethoxyethane is added dropwise and themixture is stirred, the temperature being allowed to rise to RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with DCM, the organic phase is washed with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with anEtOH/benzene mixture and the solvents are evaporated off under vacuum togive 11.2 g of the expected product in the form of a gum, which is usedas such.

[0999] D)4-(2-Amino-1,3,4-oxadiazol-5-yl)-1-(benzyloxycarbonyl)-4-phenylpiperidine

[1000] A solution of 3.39 g of cyanogen bromide in 10 ml of EtOH isadded at RT to a solution of 11.2 g of the compound obtained in theprevious step in 60 ml of EtOH and the reaction mixture is refluxed for1 hour. It is concentrated to 50 ml of EtOH and water is then addeddropwise until the volume of the reaction mixture is 400 ml. Thecrystalline product formed is filtered off, washed with water, then withDCM, with AcOEt and with ether to give 8 g of the expected product.

[1001] E) 4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidinep-toluenesulfonate

[1002] A mixture of 7.85 g of the compound obtained in the previousstep, 3.95 g of p-toluenesulfonic acid monohydrate, 0.8 g of 10%palladium on charcoal, 350 ml of 95° EtOH and 10 ml of water ishydrogenated at 50° C. and at atmospheric pressure. After 3 hours, thecatalyst is filtered off on Célite® and the filtrate is concentratedunder vacuum. The residue is taken up with acetone and the crystallineproduct formed is filtered off and washed with acetone and then withether to give 7.65 g of the expected product, m.p.=183-185° C.

PREPARATION 1.16 4-Carbamoyl-4-(morpholin-4-yl)piperidine

[1003] A) 1-Benzyl-4-cyano-4-(morpholin-4-yl)piperidine

[1004] 2.5 ml of morpholine and then 5.1 g of Na₂S₂O₅ are added to amixture of 5 g of 1-benzylpiperid-4-one and 1.9 g of potassium cyanidein 50 ml of an EtOH/water mixture (50/50; v/v) and the resulting mixtureis heated at 60° C. for 2 hours. A further 2.5 ml of morpholine areadded and the reaction mixture is stirred overnight at RT. Water isadded and the crystalline product formed is filtered off to give 5.5 gof the expected product.

[1005] B) 1-Benzyl-4-carbamoyl-4-(morpholin-4-yl)piperidine

[1006] A mixture of 14 g of the compound obtained in the previous stepand 50 ml of 95% sulfuric acid is heated at 100° C. for 2 hours. Aftercooling to RT, the reaction mixture is poured onto 100 g of ice, the pHis brought to 7 by the addition of concentrated NOH solution, themixture is extracted with DCM, the organic phase is washed with waterand dried over Na₂SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica H using a DCM/MeOH mixture(100/5; v/v to 100/10; v/v) as the eluent to give 3.4 g of the expectedproduct after crystallization from iso ether.

[1007] C) 4-Carbamoyl-4-(morpholin-4-yl)piperidine

[1008] 3.1 g of ammonium formate and 0.8 g of 5% palladium on charcoalare added to a solution of 3.4 g of the compound obtained in theprevious step in 50 ml of MeOH and the mixture is stirred for 2 hours atRT. The catalyst is filtered off on Célite® and the filtrate isevaporated under vacuum to give 2.2 g of the expected product aftercrystallization from propan-2-ol.

PREPARATIONS 1.17 to 1.21

[1009] The following are obtained by carrying out the proceduredescribed in PREPARATION 1.16 and replacing the morpholine in step Awith thiomorpholine, azetidine, pyrrolidine, perhydroazepine,di-n-heptylamine and di-n-butylamine:

[1010] 4-carbamoyl-4-(thiomorpholin-4-yl)piperidine (1.17);

[1011] 4-carbamoyl-4-(azetidin-1-yl)piperidine (1.18);

[1012] 4-carbamoyl-4-(perhydroazepin-1-yl)piperidine (1.19);

[1013] 4-carbamoyl-4-(di-n-heptylamino)piperidine (1.20);

[1014] 4-carbamoyl-4-(di-n-butylamino)piperidine (1.21).

PREPARATIONS 1.22 to 1.26

[1015] The following are obtained by carrying out the proceduredescribed in PREPARATION 1.9, starting from the1,4-dibenzyl-4-carboxypiperidine obtained in step A of PREPARATION 1.6and replacing the pyrrolidine with azetidine, piperidine, morpholine,perhydroazepine and 1-methylpiperazine:

[1016] 4-benzyl-4-(azetidin-1-ylcarbonyl)piperidine p-toluenesulfonate(1.22);

[1017] 4-benzyl-4-(piperidin-1-ylcarbonyl)piperidine p-toluenesulfonate(1.23);

[1018] 4-benzyl-4-(morpholin-4-ylcarbonyl)piperidine p-toluenesulfonate(1.24);

[1019] 4-benzyl-4-(perhydroazepin-1-ylcarbonyl)piperidinep-toluenesulfonate (1.25);

[1020] 4-benzyl-4-(4-methylpiperazin-1-ylcarbonyl)piperidinep-toluenesulfonate (1.26).

PREPARATIONS 1.27 to 1.31

[1021] The following are obtained by carrying out the proceduredescribed in PREPARATION 1.11, steps B and C, and replacing thepyrrolidine in step B with azetidine, piperidine, morpholine,perhydroazepine and 1-methylpiperazine:

[1022] 4-(azetidin-1-ylcarbonyl)-4-phenylpiperidine (1.27);

[1023] 4-(piperidin-1-ylcarbonyl)-4-phenylpiperidine (1.28);

[1024] 4-(morpholin-4-ylcarbonyl)-4-phenylpiperidine (1.29);

[1025] 4-(perhydroazepin-1-ylcarbonyl)-4-phenylpiperidine (1.30);

[1026] 4-(4-methylpiperazin-1-ylcarbonyl)-4-phenylpiperidine (1.31).

PREPARATION 1.32 4-(N-Methylcarbamoyl)-4-phenylpiperidine

[1027] A) 1-tert-Butoxycarbonyl-4-(N-methylcarbamoyl)-4-phenylpiperidine

[1028] 1.98 g of triethylamine and then 0.49 g of methylaminehydrochloride are added to a solution of 1.5 g of the compound obtainedin step A of PREPARATION 1.11 in 5 ml of DCM and 5 ml of DMF. Themixture is cooled in an ice bath, 2.39 g of BOP are added and thereaction mixture is stirred for 24 hours, the temperature being allowedto rise to RT. It is concentrated under vacuum and the residue isextracted with ether, washed with water and with saturated NaClsolution, dried over MgSO₄ and evaporated under vacuum to give 1.4 g ofthe expected product.

[1029] B) 4-(N-Methylcarbamoyl)-4-phenylpiperidine

[1030] 4 ml of concentrated HCl are added to a solution of 1.4 g of thecompound obtained in the previous step in 30 ml of MeOH and the mixtureis stirred for 1 hour at RT. It is concentrated under vacuum, theresidue is extracted with DCM, washed with water and twice with 10% NaOHsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 0.6 g of the expected product.

PREPARATION 1.33 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine

[1031] A)1-tert-Butoxycarbonyl-4-(N-n-butylcarbamoyl)-4-phenylpiperidine

[1032] This compound is prepared by the procedure described in step A ofPREPARATION 1.32, starting from 1.0 g of the compound obtained in step Aof PREPARATION 1.11 and 0.24 g of n-butylamine. This gives 1.3 g of theexpected product, which is used as such in the next step.

[1033] B) 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine

[1034] This compound is prepared by the procedure described in step B ofPREPARATION 1.32. This gives 0.4 g of the expected product.

PREPARATION 1.34 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidinetrifluoroacetate

[1035] A)1-tert-Butoxycarbonyl-4-(N,N-diethylcarbamoyl)-4-phenylpiperidine

[1036] This compound is prepared by the procedure described in step A ofPREPARATION 1.32, starting from 1.5 g of the compound obtained in step Aof PREPARATION 1.11 and 0.8 g of diethylamine hydrochloride. This gives1.7 g of the expected product.

[1037] B) 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidine trifluoroacetate

[1038] 1.7 g of the compound obtained in the previous step are dissolvedin 20 ml of trifluoroacetic acid and the solution is stirred at RT for30 minutes. It is concentrated under vacuum, the residue is taken upwith ether and the mixture is evaporated under vacuum to give 2.8 g ofthe expected product in the form of an oil.

PREPARATION 1.35 4-Carbamoyl-4-phenylpiperidine

[1039] A) 1-tert-Butoxycarbonyl-4-carbamoyl-4-phenylpiperidine

[1040] A solution of 1.5 g of the compound obtained in step A ofPREPARATION 1.11, 0.99 g of triethylamine and 2.39 g of BOP in 10 ml ofDCM is cooled to −20° C. and ammonia gas is then bubbled into thesolution. The temperature is allowed to rise to RT and the reactionmixture is stirred for 2 hours. It is concentrated under vacuum, theresidue is extracted with ether, the organic phase is washed with water,with a buffer solution of pH 2, with water, with 10% NaOH solution, withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 1.32 g of the expectedproduct.

[1041] B) 4-Carbamoyl-4-phenylpiperidine

[1042] This compound is prepared by the procedure described in step B ofPREPARATION 1.32, starting from 1.32 g of the compound obtained in theprevious step. This gives 0.41 g of the expected product.

PREPARATION 1.36 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine

[1043] A)1-tert-Butoxycarbonyl-4-(N-isopropylcarbamoyl)-4-phenylpiperidine

[1044] This compound is prepared by the procedure described in step A ofPREPARATION 1.32, starting from 1.5 g of the compound obtained in step Aof PREPARATION 1.11 and 0.29 g of isopropylamine. This gives 1.61 g ofthe expected product.

[1045] B) 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine

[1046] This compound is prepared by the procedure described in step B ofPREPARATION 1.32, starting from 1.61 g of the compound obtained in theprevious step. This gives 1.1 g of the expected product.

PREPARATION 2.1 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidinehydrochloride

[1047] A) Methyl 4-cyano-4-(3,4-dichlorophenyl)heptanedioate

[1048] In a three-necked flask, 37.2 g of 3,4-dichlorophenylacetonitrileand 34.43 g of methyl acrylate are dissolved in 20 ml of dioxane; 1 mlof DBU is added and the mixture is heated for 2 hours at 60° C.,evaporated, diluted with 400 ml of ethyl acetate, then washed withdilute HCl and NaCl solution, dried over MgSO₄ and evaporated. Theexpected product is crystallized from 100 ml of ethyl acetate and 100 mlof ether with 100 ml of heptane to give 47 g of product.

[1049] B) Methyl 3-[5-(3,4-dichlorophenyl)-2-oxopiperid-5-yl]propionate

[1050] 40 g of the compound prepared in step A are dissolved in 500 mlof 2-methoxyethanol, 2 g of Raney nickel are added and the mixture ishydrogenated at 40° C. under atmospheric pressure for 3 days. It isfiltered and evaporated to give the expected product in the form of anoil (39 g).

[1051] C) 3-[5-(3,4-Dichlorophenyl)-2-oxopiperid-5-yl]propanoic acid

[1052] 17 g of the compound prepared in the previous step are dissolvedin 250 ml of methanol, 2.8 g of potassium hydroxide and 10 ml of waterare added and the mixture is then refluxed for 2 hours. It is evaporatedto dryness and the oil obtained is taken up with 200 ml of water andwashed with 100 ml of ethyl acetate. The aqueous phase is acidified with30% HCl solution and the precipitate formed is then filtered off anddried. It is recrystallized from hot methanol to give 18.3 g of theexpected compound.

[1053] D) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidinehydrochloride

[1054] 5 g of the compound obtained in the previous step are dissolvedin 20 ml of THF, 75 ml of borane (concentration: 1 M in THF) are addedand the mixture is refluxed for 24 hours under nitrogen. 25 ml ofmethanol and 50 ml of 4 N HCl are added, the mixture is stirred for 30minutes and 40% sodium hydroxide is then added until the pH exceeds 10.The mixture is extracted 3 times with 150 ml of DCM and the organicphase is dried over MgSO₄ and evaporated. The residue is dissolved inDCM with a 4 N solution of HCl in ether. After evaporation, a foam isobtained and the expected product (4.5 g) crystallizes from anAcOEt/ether mixture.

PREPARATION 2.23-(3,4-Dichlorophenyl)-3-[3-tetrahydropyran-2-yloxy)propyl]perhydroazepine

[1055] A) Ethyl 5-cyano-5-(3,4-dichlorophenyl)pentanoate

[1056] 11.8 g of a 55% dispersion of sodium hydride in oil are suspendedin 100 ml of THF and cooled in an ice bath, a solution of 50 g of3,4-dichlorophenylaceto-nitrile in 50 ml of THF is added dropwise andthe reaction mixture is stirred for 3 hours at RT. It is cooled again inan ice bath, a solution of 52.4 g of ethyl 4-bromobutanoate in 50 ml ofTHF is added dropwise and the mixture is stirred overnight at RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with ether, the organic phase is washed with water, with abuffer solution of pH 2, with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using toluene and then atoluene/AcOEt mixture (100/5; v/v) as the eluent to give 36.9 g of theexpected product.

[1057] B) Ethyl5-cyano-5-(3,4-dichlorophenyl)-8-(tetrahydropyran-2-yloxy)octanoate

[1058] 5 g of a 55% dispersion of sodium hydride in oil are suspended in100 ml of DMF and cooled to −20° C., a solution of 25.4 g of2-(3-bromopropoxy)tetrahydropyran and 34.2 g of the compound obtained inthe previous step in 100 ml of DMF is added dropwise and the reactionmixture is stirred overnight at RT. It is concentrated under vacuum, theresidue is taken up with a mixture of water and a buffer solution of pH4 and extracted with AcOEt, the organic phase is washed with a buffersolution of pH 4, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica using toluene and then a toluene/AcOEtmixture (100/10; v/v) as the eluent to give 36 g of the expectedproduct.

[1059] C) Ethyl5-(aminomethyl)-5-(3,4-dichlorophenyl)-8-(tetrahydropyran-2-yloxy)-octanoate

[1060] 30 ml of a saturated solution of ammonia in MeOH and 2 g ofRaney® nickel are added to a solution of 16.7 g of the compound obtainedin the previous step in 200 ml of MeOH and the mixture is thenhydrogenated at 40° C. and at atmospheric pressure. The catalyst isfiltered off on Célite® and the filtrate is concentrated under vacuum.The residue is extracted with ether, the organic phase is washed withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 15.1 g of the expectedproduct.

[1061] D)6-(3,4-Dichlorophenyl)-6-[3-(tetrahydropyran-2-yloxy)propyl]perhydroazepin-2-one

[1062] A solution of 15.1 g of the compound obtained in the previousstep in 150 ml of xylene is refluxed for 48 hours. After cooling to RT,the reaction mixture is concentrated under vacuum to give 13.5 g of theexpected product.

[1063] E)3-(3,4-Dichlorophenyl)-3-[3-tetrahydropyran-2-yloxy)propyl]perhydroazepine

[1064] A solution of 14 g of the compound obtained in the previous stepin 200 ml of THF is added dropwise to a suspension of 4 g of lithiumaluminum hydride in 100 ml of THF and the mixture is then refluxed for 2hours. After cooling to RT, 4 ml of water, 12 ml of 10% NaOH solutionand 4 ml of water are added in succession. The inorganic salts arefiltered off on Célite® and the filtrate is concentrated under vacuum.The residue is extracted with DCM, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum to give 13 g of theexpected product.

EXAMPLE 11-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinehydrochloride 1.5 hydrate

[1065] A) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine

[1066] A solution of 16.22 g of the compound obtained in PREPARATION 2.1and 18.2 g of triethylamine in 250 ml of DCM is cooled in an ice bathand a solution of 14.06 g of benzoyl chloride in 10 ml of DCM is addeddropwise. The mixture is stirred for 1 hour, the temperature beingallowed to rise to RT. The excess benzoyl chloride is removed by theaddition of MeOH and the reaction mixture is then concentrated undervacuum. The residue is taken up with MeOH and the solvent is evaporatedoff under vacuum. The residue is extracted with ether, washed withwater, with 2 N HCl solution, with 5% NaHCO₃ solution and with saturatedNaCl solution, dried over MgSO₄ and evaporated under vacuum. The1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-benzoyloxypropyl)piperidine thusobtained as an intermediate is dissolved in 150 ml of MeOH, 10% NaOHsolution is added and the mixture is heated for 1 hour at 50-60° C. andconcentrated under vacuum. The residue is extracted with ether, washedwith water, with 2 N HCl solution, with 5% NaHCO₃ solution and withsaturated NaCI solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 18 g of the expected product in theform of an oil.

[1067] B)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-methanesulfonyloxy)propyl]piperidine

[1068] A solution of 16.8 g of the compound obtained in the previousstep and 5.18 g of triethylamine in 100 ml of DCM is cooled in an icebath, a solution of 5.40 g of methanesulfonyl chloride in 10 ml of DCMis added dropwise and the mixture is then stirred for 30 minutes, thetemperature being allowed to rise to RT. It is concentrated undervacuum, the residue is extracted with AcOEt, washed with water, with 2 NHCl solution and with saturated NaCl solution and dried over MgSO₄ andthe solvent is evaporated off under vacuum to give 19.6 g of theexpected product in the form of an oil.

[1069] Proton NMR spectrum at 200 MHz in DMSO-d₆

[1070] 1 to 2.35 ppm: us: 8H

[1071] 3.15 ppm: s: 3H

[1072] 3.2 to 4.6 ppm: us: 6H

[1073] 6.8 to 7.8 ppm us : 8H

[1074] C)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinehydrochloride 1.5 hydrate

[1075] 0.56 g of 4-(pyrrolidin-1-ylcarbonyl)piperidine hydrochloride isdissolved in water, the solution is rendered alkaline by the addition of10% NaOH solution and extracted with DCM, the organic phase is washedwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with 5 ml of DMFand 5 ml of acetonitrile, 1 g of the compound obtained in the previousstep and then 0.88 g of K₂CO₃ are added and the reaction mixture isheated at 100° C. for 4 hours. It is concentrated under vacuum, theresidue is taken up with water and extracted with AcOEt, the organicphase is washed with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using DCM and then a DCM/MeOH mixture(95/5; v/v) as the eluent. The product obtained is taken up with AcOEtand acidified by the addition of ethereal hydrogen chloride and theprecipitate formed is filtered off to give 0.8 g of the expectedproduct, m.p.=146° C.

EXAMPLE 21-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)propyl]-piperidinedihydrochloride hemihydrate

[1076] A mixture of 0.55 g of 4-piperidinopiperidine, 1.3 g of thecompound obtained in step B of EXAMPLE 1 and 1.14 g of K₂CO₃ in 10 ml ofa DMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 3hours. The reaction mixture is poured into water and extracted withAcOEt, the organic phase is washed twice with water and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica H using DCM andthen a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtainedis dissolved in AcOEt, a stream of HCl gas is bubbled into the solutionuntil the pH is 1, and ether is added until precipitation occurs. Thisgives 0.53 g of the expected product after filtration and drying,m.p.=265° C. (dec.).

EXAMPLE 31-Benzoyl-3-(3,4-dichlorophenyl)-[3-[4-carbamoyl-4-(piperid-1-yl)piperid-1-yl]propyl]piperidinedihydrochloride 1.5 hydrate

[1077] 2.6 g of 4-carbamoyl-4-(piperid-1-yl)piperidine dihydrochlorideare dissolved in water, the solution is rendered alkaline by theaddition of concentrated NaOH solution and extracted with DCM, theextract is dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is taken up with 10 ml of acetonitrile, 1.55 g ofthe compound obtained in step B of EXAMPLE 1 are added and the reactionmixture is refluxed for 2 hours. It is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with water,with 1 N NaOH solution and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using a gradient of a DCM/MeOH mixture(99/1; v/v to 93/7; v/v) as the eluent. The product obtained is taken upwith DCM and acidified by the addition of ethereal hydrogen chloride andthe mixture is evaporated under vacuum to give 2 g of the expectedproduct, m.p.=210° C.

EXAMPLE 43-[3-[4-(Acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride

[1078] A mixture of 0.27 g of4-(acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride, 0.45 g ofthe compound obtained in step B of EXAMPLE 1 and 0.3 g of K₂CO₃ in 3 mlof DMF is heated at 80° C. for 2 hours. The reaction mixture is pouredinto water and extracted with AcOEt, the organic phase is washed withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using a gradient of a DCM/MeOH mixture (99/1; v/v to 95/5;v/v) as the eluent. The product obtained is dissolved in DCM andacidified by the addition of ethereal hydrogen chloride and theprecipitate formed is filtered off to give 0.2 g of the expectedproduct, m.p.=128° C.

EXAMPLE 53-[3-[4-(2-Aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinedihydrochloride monohydrate

[1079] A mixture of 1.04 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine(compound of PREPARATION 1.4 in the form of the free base), 1.88 g ofthe compound obtained in step B of EXAMPLE 1 and 1.1 g of K₂CO₃ in 20 mlof a DMF/acetonitrile mixture (50/50; v/v) is refluxed for 2 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upwith water and extracted with AcOEt, the organic phase is washed withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a gradient of aDCM/MeOH mixture (98/2; v/v to 95/5; v/v) as the eluent. The productobtained is taken up with ethereal hydrogen chloride and the precipitateformed is filtered off to give 1.2 g of the expected product aftercrystallization from AcOEt, m.p.=162-164° C.

EXAMPLE 6 3-[3-(4-Acetyl-4-benzylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride hemihydrate

[1080] 1.2 g of 4-acetyl-4-benzylpiperidine hydrochloride are dissolvedin the minimum amount of water, the solution is rendered alkaline to pH13 by the addition of concentrated NaOH solution and extracted withether and the organic phase is dried over MgSO₄ and filtered. 1 g of thecompound obtained in step B of EXAMPLE 1 is added to the filtrate andthe mixture is concentrated under vacuum. The residue is taken up with 5ml of DMF and heated at 70° C. for 3 hours. The reaction mixture ispoured into iced water and extracted with ether, the organic phase iswashed with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture (95/5;v/v) as the eluent. The product obtained is taken up with DCM andacidified to pH 1 by the addition of ethereal hydrogen chloride and themixture is evaporated under vacuum to give 0.84 g of the expectedproduct after crystallization from iso ether.

[1081] Proton NMR spectrum at 200 MHz in DMSO-d₆

[1082] 0.9 to 2.4 ppm: us: 15H

[1083] 2.5 to 4.6 ppm: us: 12H

[1084] 6.8 to 7.9 ppm :us; 13H

[1085] 9.9 to 10.6 ppm : 2 bs: 1H

EXAMPLE 73-[3-[4-(Acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride dihydrate

[1086] A mixture of 0.44 g of 4-(acetylamino)-4-benzylpiperidinep-toluene-sulfonate, 0.50 g of the compound obtained in step B ofEXAMPLE 1 and 0.53 g of K₂CO₃ in 5 ml of DMF is heated at 90° C. for 2hours. The reaction mixture is poured into water and extracted withAcOEt, the organic phase is washed with 2 N NaOH and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using a gradient of aDCM/MeOH mixture (99/1; v/v to 93/7; v/v) as the eluent. The productobtained is dissolved in DCM and acidified by the addition of etherealhydrogen chloride and the precipitate formed is filtered off to give0.38 g of the expected product, m.p=158° C. (dec.).

EXAMPLE 81-Benzoyl-3-[3-(4-benzyl-4-cyanopiperid-1-yl)propyl]-3-(3,4-dichloro-phenyl)piperidinehydrochloride monohydrate

[1087] This compound is prepared by the procedure described in EXAMPLE4, starting from 2.5 g of 4-benzyl-4-cyanopiperidine, 5 g of thecompound obtained in step B of EXAMPLE 1, 3.7 g of K₂CO₃ and 50 ml ofDMF. The product obtained is chromatographed on silica H using DCM andthen a DCM/MeOH mixture (97/3; v/v) as the eluent. The product obtainedis taken up with ethereal hydrogen chloride and the solvent isevaporated off under vacuum to give 2.8 g of the expected product aftercrystallization from iso ether.

EXAMPLE 93-[3-[4-(Aminomethyl)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinedihydrochloride hemihydrate

[1088] A mixture of 2.3 g of the compound obtained in EXAMPLE 8 and 0.3g of Raney® nickel in 100 ml of EtOH is hydrogenated for 72 hours at RTand at atmospheric pressure. The catalyst is filtered off and thefiltrate is concentrated under vacuum. The residue is chromatographed onsilica H using DCM and then a DCM/MeOH mixture (85/15; v/v) as theeluent. The product obtained is taken up with ethereal hydrogen chlorideand the precipitate formed is filtered off to give 1.08 g of theexpected product.

[1089] Proton NMR spectrum at 200 MHz in DMSO-d₆

[1090] 0.8 to 2.3 ppm :us: 12H

[1091] 2.6 to 4.5 ppm : us: 14H

[1092] 6.9 to 8.0 ppm: us: 13H

[1093] b 8.4ppm:bs:3H

EXAMPLE 101-Benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidinehydrochloride

[1094] A solution of 0.6 g of the compound obtained in EXAMPLE 9 and0.18 ml of triethylamine in 10 ml of DCM is cooled to 0° C., 0.1 ml ofpropionyl chloride is added dropwise and the mixture is stirred for 5minutes. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed twice with water and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture (9515;v/v) as the eluent. The product obtained is taken up with etherealhydrogen chloride and the precipitate formed is filtered off to give0.37 g of the expected product.

[1095] Proton NMR spectrum at 200 MHz in DMSO-d6

[1096] 0.7 to 2.3 ppm: us: 17H

[1097] b 2.55to4.5ppm:us: 14H

[1098] 6.8 to 8.0 ppm: us: 14H

[1099] 9.0to 10ppm:2bs: 1H

EXAMPLE 111-Benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidinehydrochloride hemihydrate

[1100] This compound is prepared by the procedure described in EXAMPLE7, starting from 0.5 g of 4-benzyl-4-(ethoxycarbonylamino)piperidinep-toluene-sulfonate, 0.5 g of the compound obtained in step B of EXAMPLE1 and 0.52 g of K₂CO₃ in 5 ml of DMF. This gives 0.32 g of the expectedproduct, m.p.=142° C. (dec.).

EXAMPLE 121-Benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidinehydrochloride hemihydrate

[1101] A mixture of 4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidinep-toluene-sulfonate, 0.65 g of the compound obtained in step B ofEXAMPLE 1 and 0.7 g of K₂CO₃ in 6 ml of DMF is heated at 80° C. for 3hours. The reaction mixture is poured into iced water andthe precipitateformed is filtered off and washed with water. The precipitate isdissolved in AcOEt, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using DCM and then a DCM/MeOH mixture (95/5; v/v) as theeluent. The product obtained is taken up with ethereal hydrogen chlorideand the precipitate formed is filtered off to give 0.56 g of theexpected product.

[1102] Proton NMR spectrum at 200 MHz in DMSO-d₆

[1103] 0.9 to 2.45 ppm : us: 16H

[1104] 2.5 to 4.6 ppm: us: 16H

[1105] 6.8 to 7.8 ppm: us: 13H

[1106] 9.9 to 10.6 ppm: rs: 1H

EXAMPLE 133-[3-[4-(Acetyl-N-methylamino)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)perhydroazepinehydrochloride 0.3 hydrate

[1107] A)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-(tetrahydropyran-2-yloxy)propyl]-perhydroazepine

[1108] A solution of 13 g of the compound obtained in PREPARATION 2.2and 6.8 g of triethylamine in 200 ml of DCM is cooled in an ice bath, asolution of 4.96 g of benzoyl chloride in 30 ml of DCM is added dropwiseand the reaction mixture is stirred for 5 minutes. It is concentratedunder vacuum, the residue is taken up with water and extracted withAcOEt, the organic phase is washed with water, with 5% NaHCO₃ solution,with water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 16.5 g of the expectedproduct.

[1109] B)1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)perhydroazepine

[1110] A stream of HCl gas is bubbled into a solution of 16.5 g of thecompound obtained in the previous step in 200 ml of MeOH until the pH is<1, and the reaction mixture is stirred for 10 minutes. It isconcentrated under vacuum, the residue is taken up with a saturatedsolution of HCl gas in MeOH and the solvent is evaporated off undervacuum. The residue is extracted with DCM, the organic phase is washedwith 5% NaHCO₃ solution and with saturated NaCi solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 13.7 g ofthe expected product.

[1111] C)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-methanesulfonyloxy)propyl]-perhydroazepine

[1112] A solution of 5 g of the compound obtained in the previous stepand 1.5 g of triethylamine in 100 ml of DCM is cooled in an ice bath, asolution of 1.55 g of methanesulfonyl chloride in 20 ml of DCM is addeddropwise and the mixture is stirred for 5 minutes. It is concentratedunder vacuum, the residue is taken up with water and extracted withAcOEt, the organic phase is washed with water, with 5% NaHCO₃ solution,with water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 5.7 g of the expectedproduct.

[1113] D)3-[3-[4-(Acetyl-N-methylamino)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)perhydroazepinehydrochloride 0.3 hydrate

[1114] A mixture of 1.2 g of 4-(acetyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate, 1.2 g of the compound obtained in the previous stepand 1.2 g of K₂CO₃ in 20 ml of a DMF/acetonitrile mixture (50150; v/v)is refluxed for 3 hours. After cooling to RT, the reaction mixture ispoured into water and extracted with AcOEt, the organic phase is washedthree times with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using DMC and then a DCM/MeOH mixture (96/4;v/v) as the eluent. The product obtained is taken up with etherealhydrogen chloride and the solvent is evaporated off under vacuum to give0.63 g of the expected product after solidification in ether, m.p.=125°C.

EXAMPLE 141-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(N,N-dimethylaminocarbonyl)-4-phenylpiperid-1-yl]propyl]perhydroazepinehydrochloride hemihydrate

[1115] This compound is prepared by the procedure described in step D ofEXAMPLE 13, starting from 0.69 g of4-(N,N-dimethylaminocarbonyl)-4-phenyl-piperidine, 1.2 g of the compoundobtained in step C of EXAMPLE 13 and 1.2 g of K₂CO₃ in 20 ml of aDMF/acetonitrile mixture (50/50; v/v). This gives 0.65 g of the expectedproduct, m.p.=150° C.

EXAMPLE 151-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-yl-carbonyl)piperid-1-yl]propyl]perhydroazepinehydrochloride hemihydrate

[1116] This compound is prepared by the procedure described in step D ofEXAMPLE 13, starting from 0.96 g of4-phenyl-4-(pyrrolidin-1-ylcarbonyl)-piperidine, 1.5 g of the compoundobtained in step C of EXAMPLE 13 and 1.5 g of K₂CO₃ in 10 ml of aDMF/acetonitrile mixture (50/50; v/v). This gives 0.34 g of the expectedproduct, m.p.=135° C.

EXAMPLE 163-[3-[4-(2-Aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)perhydroazepinedihydrochloride 1.5 hydrate

[1117] This compound is prepared by the procedure described in step D ofEXAMPLE 13, starting from 0.77 g of4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4in the form of the free base), 1.2 g of the compound obtained in step Cof EXAMPLE 13 and 1.2 g of K₂CO₃ in 20 ml of a DMF/acetonitrile mixture(50/50; v/v). This gives 0.8 g of the expected product aftercrystallization from AcOEt, m.p.=178° C.

EXAMPLE 171-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenyl-piperid-1-yl]propyl]piperidinehydrochloride monohydrate

[1118] A mixture of 1 g of 4-(2-hydroxyethoxy)-4-phenylpiperidinehydrochloride, 1.7 g of the compound obtained in step B of EXAMPLE 1 and0.65 g of K₂CO₃ in 15 ml of DMF is heated at 60° C. for 2 hours and thereaction mixture is then stirred overnight at RT. It is poured intowater and extracted with DCM, the organic phase is washed with water anddried over Na₂SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H using DCM and then a DCM/MeOHmixture (96/4; v/v) as the eluent. The product obtained is dissolved inDCM and acidified by the addition of ethereal hydrogen chloride and theprecipitate formed is filtered off to give 1.2 g of the expectedproduct, m.p.=120-123° C.

EXAMPLE 18 3-[3-[4-(2-Acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride 1.5 hydrate

[1119] A solution of 0.6 g of the compound obtained in EXAMPLE 17 and0.5 ml of triethylamine in 25 ml of DCM is cooled to 0-5° C., 0.085 mlof acetyl chloride is added and the mixture is stirred for 3 hours, thetemperature being allowed to rise to RT. It is concentrated undervacuum, the residue is taken up with water and extracted with AcOEt, theorganic phase is washed with water and dried over Na₂SO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. Theproduct obtained is dissolved in DCM and acidified by the addition ofethereal hydrogen chloride and the precipitate formed is filtered off togive 1.2 g of the expected product, m.p.=105-107° C.

EXAMPLE 191-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidinehydrochloride hemihydrate

[1120] A)3-[3-(4-Amino-4-phenylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichlorophenyl)-piperidine

[1121] A mixture of 6.81 g of 4-amino-4-phenylpiperidinedibenzenesulfonate, 5.2 g of the compound obtained in step B of EXAMPLE1 and 6.1 g of K₂CO₃ in 30 ml of a DMF/acetonitrile mixture (50/50; v/v)is heated at 100° C. for 5 hours. It is concentrated under vacuum, theresidue is taken up with water and extracted with AcOEt, the organicphase is washed with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a DCM/MeOH mixture (from 99/1; v/vto 85/15; v/v) as the eluent to give 3.6 g of the expected product.

[1122] B)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidinehydrochloride hemihydrate

[1123] A solution of 1.5 g of the compound obtained in the previous stepand 0.54 g of triethylamine in 10 ml of DCM is cooled to 0-5° C., 0.35 gof 2-furoyl chloride is added and the mixture is stirred for 2 hours 30minutes, the temperature being allowed to rise to RT. It is concentratedunder vacuum, the residue is extracted with DCM, the organic phase iswashed with water, with 5% NaHCO₃ solution, with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing DCM and then a DCM/MeOH mixture (97/3; v/v) as the eluent. Theproduct obtained is dissolved in AcOEt, a stream of HCl gas is bubbledinto the solution until the pH is 1, and ether is added untilprecipitation occurs. This gives 1.27 g of the expected product afterfiltration and drying, m.p.=180-182° C.

EXAMPLE 201-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid-1-yl]propyl]piperidinehydrochloride monohydrate

[1124] This compound is prepared by the procedure described in step B ofEXAMPLE 19, starting from 1.5 g of the compound obtained in step A ofEXAMPLE 19, 0.55 g of triethylamine and 0.4 g of 2-thenoyl chloride in10 ml of DCM. The residue is chromatographed on silica H using DCM andthen a DCM/MeOH mixture (95/5; v/v) as the eluent. The product obtainedis taken up with DCM and acidified to pH I by the addition of etherealhydrogen chloride and the precipitate obtained is filtered off to give0.99 g of the expected product, m.p.=198-200° C.

EXAMPLE 213-(3,4-Dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinedihydrochloride trihydrate, (+) isomer (compound of formula I^(••)a,Z^(••)=4-pyridyl)

[1125] A) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidinehydrochloride, (+) isomer

[1126] 5 ml of 40% NaOH solution are added to a solution of 10 g of thecompound obtained in PREPARATION 2.1 in 20 ml of water, the mixture isextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 9 g of an oil. 2.7 g ofthe oil obtained are dissolved in 50 ml of propan-2-ol, 2.36 g of10-camphosulfonic acid, (+) isomer, are added and the mixture is heatedto the reflux temperature. After cooling, crystallization and filtrationof the crystals formed (3.86 g), the latter are dissolved in 10% NaOHsolution and extracted with chloroform, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum to give 2.3 g ofproduct in the form of an oil, from which the hydrochloride is prepared.The optical rotation of the hydrochloride is measured.

[1127] [α]_(D) ²⁵=+5.5° (c=0.1; MeOH)

[1128] A second crystallization is carried out using 2.12 g of the oilobtained and 1.84 g of 10-camphosulfonic acid, (+) isomer, in 40 ml ofpropan-2-ol. After alkalization with NaOH, extraction with chloroform,drying over MgSO₄ and evaporation, 2.1 g of the expected product areobtained in the form of an oil, from which the hydrochloride isprepared.

[1129] [α]_(D) ²⁵=+6.5° (c=0.1; MeOH)

[1130] B)1-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine,(+) isomer

[1131] 0.61 g of di-tert-butyl dicarbonate is added to a solution of 0.9g of the compound obtained in the previous step and 0.6 g oftriethylamine in 100 ml of DCM and the mixture is stirred for 30 minutesat RT. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with a buffer solution of pH 2, with1 N NaOH solution and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum to give 1.1 g of theexpected product in the form of an oil.

[1132] C)1-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-[3-(methanesulfonyloxy)-propyl]piperidine,(+) isomer

[1133] A solution of 22 g of the compound obtained in the previous stepand 6.86 g of triethylamine in 150 ml of DCM is cooled to 0-5° C., 7.13g of methanesulfonyl chloride are added and the mixture is stirred for 1hour at 0-5° C. and then for 2 hours at RT. It is concentrated undervacuum. the residue is extracted with AcOEt, the organic phase is washedwith water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The product obtained is taken upwith ether and the mixture is then evaporated under vacuum to give 26.4g of the expected product in the form of an oil.

[1134] D)1-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine,(+) isomer

[1135] A mixture of 17 g of4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine, 25.5 g of the compoundobtained in the previous step and 22.7 g of K₂CO₃ in 100 ml of aDMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 3 hours30 minutes. It is concentrated under vacuum, the residue is extractedwith AcOEt, the organic phase is washed with water and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is taken up with pentane and the precipitateformed is filtered off to give 33 g of the expected product,m.p.=133-137° C.

[1136] [α]_(D) ²⁰=+33.2° (c=0.5; MeOH)

[1137] E)3-(3,4-Dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinedihydrochloride, (+) isomer

[1138] Concentrated HCl solution is added to a solution of 25.8 g of thecompound obtained in the previous step in 200 ml of MeOH until the pH is1, and the mixture is heated at 40° C. for 3 hours. It is concentratedunder vacuum and the product obtained is crystallized from anAcOEt/ether mixture to give 17 g of the expected product, m.p.=170° C.

[1139] [α]_(D) ²⁰=+13° (c=0.5; MeOH)

[1140] F)3-(3,4-Dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-yl-carbonylpiperid-1-yl]propyl]piperidinedihydrochloride trihydrate, (+) isomer

[1141] A solution of 1.7 g of the compound obtained in the previous stepand 0.9 g of triethylamine in 10 ml of DCM is cooled to 0-5° C., 0.6 gof isonicotinoyl chloride hydrochloride is added and the mixture isstirred for 1 hour at RT. It is concentrated under vacuum, the residueis extracted with AcOEt, the organic phase is washed with water and withsaturated NaCl solution and dried over Na₂SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing DCM and then a DCM/MeOH mixture (93/7; v/v) as the eluent. Theproduct obtained is dissolved in AcOEt, a stream of HCl gas is bubbledinto the solution until the pH is 1, and ether is added untilprecipitation occurs. This gives 0.27 g of the expected product afterfiltration and drying, m.p.=140-142° C.

[1142] [α]_(D) ²⁰=+11.6° (c=0.5; MeOH)

EXAMPLE 221-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[spiro(indoline-3,4′-piperid-1′-yl)-propyl]piperidinedihydrochloride 1.5 hydrate

[1143] A mixture of 1 g of the compound obtained in step B of EXAMPLE 1,0.7 g of spiro(indoline-3,4′-piperidine) dihydrochloride and 0.8 g ofK₂CO₃ in 10 ml of DMF is heated at 70-80° C. for 3 hours. The reactionmixture is poured into water and the precipitate formed is filtered offand dried. The precipitate is chromatographed on silica using DCM andthen a DCM/MeOH mixture (94/6; v/v) as the eluent. The product obtainedis dissolved in DCM and acidified to pH 1 by the addition of etherealhydrogen chloride and the precipitate formed is filtered off to give 0.5g of the expected product, m.p.=192-195° C.

EXAMPLE 231-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4′-piperid-1′-yl)propyl]piperidinehydrochloride monohydrate

[1144] A mixture of 1 g of the compound obtained in step B of EXAMPLE 1,1 g of 1-acetylspiro(indoline-3,4′-piperidine) hydrochloride and 0.6 gof K₂CO₃ in 10 ml of DMF is heated at 70° C. for 2 hours. The reactionmixture is poured into water and the precipitate formed is filtered off.The precipitate is dissolved in DCM, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using DCM and then a DCM/MeOH mixture (97/3;v/v) as the eluent. The product obtained is dissolved in DCM andacidified to pH 1 by the addition of ethereal hydrogen chloride and theprecipitate formed is filtered off to give 0.7 g of the expectedproduct, m.p.=189-191° C.

[1145] The compounds according to the invention collated in TABLE Ibelow are prepared by following the procedure described in step F ofEXAMPLE 21, starting from the compound obtained in step E of EXAMPLE 21and the appropriate acid chlorides. TABLE I (I^(··)a)

Salt, solvate; m.p. ° C.; Example Z^(··) [α]_(D) ²⁰ 24

HCl, 1H₂O; 134-136; +31° (c = 0.5; MeOH) 25

HCl, 0.5H₂O; 172; +35.6° (c = 0.5; MeOH) 26

HCl, 1.25H₂O; 120-122; +47° (c = 0.5; MeOH) 27

HCl, 2H₂O; 175; +32.6° (c = 0.5; MeOH)

[1146] The compounds according to the invention collated in TABLE IIbelow are prepared by following the procedures described in the previousEXAMPLES, starting from the compound obtained in step B of EXAMPLE 1 andthe piperidines described in the REPARATIONS. TABLE II (I)

Salt, solvate; Example B- m.p. ° C. or NMR 28 (a)

2HCl, 2.5H₂O; 202-204 29 (b)

HCl, H₂O; 160-162 30 (a)

2HCl, H₂O; 165 31 (c)

HCl, 1.2H₂O; 175-180 32 (c)

HCl, 0.5H₂O; 155-157 33 (c)

HCl, 1.3H₂O; 158-160

1. A compound of the formula

in which: R₁ is hydrogen; R₂ is the methyl group; or R₁ and R₂ togetherform a group —(CH₂)₃— or —(CH₂)₄—; Ar₁ is a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a(C₁-C₄)alkyl, a trifluoromethyl and a methylenedioxy, said substituentsbeing identical or different; a thienyl which is unsubstituted orsubstituted by a halogen atom; a benzothienyl which is unsubstituted orsubstituted by a halogen atom; a naphthyl which is unsubstituted orsubstituted by a halogen atom; an indolyl which is unsubstituted orN-substituted by a (C₁-C₄)alkyl or a benzyl; an imidazolyl which isunsubstituted or substituted by a halogen atom; a pyridyl which isunsubstituted or substituted by a halogen atom; or a biphenyl; T is agroup —CH₂—; a group —CO—; a group —COO—; or a group —CONR₃— in which R₃is a hydrogen or a (C₁-C₄)alkyl; A is a direct bond; a group—(CH₂)_(t)—, in which t is one, two or three; or a vinylene group; or—T—A— is the group —SO₂—; Z is an optionally substituted, mono-, di- ortri-cyclic aromatic or heteroaromatic group; and B is:

in which: x is zero or one; Ar₂ is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (C₁-C₄)alkyl, a(C₁-C₄)alkoxy and a methylenedioxy, said substitaents being identical ordifferent; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which isunsubstituted or substituted by a (C₁-C₄)alkyl; and X₁ is a groupselected from: (1) hydrogen; (2) (C₁-C₇)alkyl; (3) formyl; (4)(C₁-C₇)atkylcarbonyl; (5) —(CH₂)_(m)—OR₄; (6) —(CH₂)_(m)—OCOR₅; (7)—(CH₂)_(m)—OCONH—(C₁-C₇)alkyl; (8) —O—CH₂CH₂—OR₆; (9) —(CH₂)_(n)—SR₇;(10) —CH₂—S(O)_(j)—(C₁-C₇)alkyl; (11) —NR₈R₉; (12) —(CH₂)_(p)—NR₁₀R₁₁;(13) —NR₁₂COR₁₃; (14) —NR₁₄COCOR₁₅; (15) —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆; (16)—(CH₂)_(m)—NR₁₄COOR₁₇; (17) —(CH₂)_(m)—NR₁₄SO₁₂R₁₈; (18)(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀; (19) —(CH₂)_(n)—COOR₂₁; (20)—(CH₂)_(n)—C(═W₁)NR₁₉R₂₀; (21) —CO—NR₂₂—NR₂₃R₂₄; (22) —CN;

or X₁ forms a double bond between the carbon atom to which it is bondedand the adjacent carbon atom of the piperidine ring; in which groups: mis zero, one or two; n is zero or one; p is one or two; j is one or two;W₁ is an oxygen atom or a sulfur atom; R₄ is a hydrogen or a(C₁-C₇)alkyl; R₅ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;or a pyridyl; R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl; R₇ is a hydrogen or a (C₁-C₇)alkyl; R₈ and R₉ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₉ can also be a(C₃-C₇)cycloalkylmethyl, a benzyl or a phenyl; or R₈ and R₉, togetherwith the nitrogen atom to which they are bonded, form a heterocycleselected from azetidine, pyrrolidine, piperidine, morpholine,thiomorpholine, perhydroazepine and piperazine which is unsubstituted orsubstituted in the 4-position by a (C₁-C₄)alkyl; R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a(C₃-C₇)cycloalkylmethyl or a benzyl; R₁₂ is a hydrogen or a(C₁-C₇)alkyl; R₁₃ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or animidazolyl; or R₁₂ and R₁₃ together are a group —(CH₂)_(u)—, in which uis three or four; R₁₄ is a hydrogen or a (C₁-C₇)alkyl; R₁₅ is a(C₁-C₄)alkoxy; R₁₆ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or animidazolyl; R₁₇ is a (C₁-C₇)alkyl or a phenyl; R₁₈ is a (C₁-C₇)alkyl; anamino which is free or substituted by one or two (C₁-C₇)alkyls; or aphenyl which is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a (C₁-C₇)alkyl, atrifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a(C₁-C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro andan amino which is free or substituted by one or two (C₁-C₇)alkyls, saidsubstituents being identical or different; R₁₉ and R₂₀ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₂₀ can also be a(C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a(C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; R₂₁ is a hydrogen or a (C₁-C₇)albyl; R₂₂ is a hydrogen ora (C₁-C₇)alkyl; R₂₃ and R₂₄ are each independently a hydrogen or a(C₁-C₇)alkyl; R₂₅ is a hydrogen or a (C₁-C₇)alkyl; and R₂₆ and R₂₇ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be aformyl or a (C₁-C₇)alkylcarbonyl;

in which Ar₂ is as defined above;

in which Ar₂ is as defined above;

in which Ar₂ is as defined above;

in which: Ar₂ is as defined above; Am₁ is an amino group substituted bytwo (C₁-C₄)alkyls; and r is two or three; i₆—or a group Ar₂—W₂—CH— inwhich: Ar₂ is as defined above; W₂ is an oxygen atom; a sulfur atom; asulfinyl; a sulfonyl; or a group —NL₁—; L₁ is a hydrogen; a(C₁-C₄)alkyl; a (C₁-C₄)alkylcarbonyl; or a group —(CH₂)_(v)—Am₂; v isone, two or three; and Am₂ is an amino group which is unsubstituted ormonosubstituted or disubstituted by a (C₁-C₄)alkyl; Am₂ can also be apyrrolidino, piperidino or morpholino group; ii—or a group B₂ of theformula

in which J₂ is:

in which: Ar₂ is as defined above; r is two or three; and Am₁ is asdefined above; iii—or a group B₃ of the formula

in which J₃ is:

a group: in which: W₃ is an oxygen atom; a sulfur atom; or a group NR₃₀,in which R₃₀ is a hydrogen or a (C₁-C₃)alkyl; R₂₈ is a hydrogen; a(C₁-C₆)alkyl; a (C₃-C₆)alkenyl in which one vinylic carbon atom is notbonded to the nitrogen atom; a 2-hydroxyethyl; a (C₃-C₇)cycloalkyl; aphenyl which is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a trifluoromethyl, a(C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a nitro, an amino and a hydroxyl, saidsubstituents being identical or different; or a 6-membered heteroarylcontaining one or two nitrogen atoms as heteroatoms, said heteroarylbeing unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a trifluoromethyl, a(C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a nitro, an amino and a hydroxyl, saidsubstituents being identical or different; R₂₉ is a hydrogen; a(C₁-C₆)alkyl which is unsubstituted or substituted by a hydroxyl and/orby one, two or three fluorine atoms; a (C₃-C₆)cycloalkyl; a(C₁-C₅)alkoxy (only when W₃ is an oxygen atom); a (C₃-C₆)cycloalkoxy(only when W₃ is an oxygen atom); or a group —NR₃₁R₃₂ containing fromzero to seven carbon atoms, R₂₉ being other than an unsubstituted(C₁-C₄)alkyl when simultaneously W₃ is an oxygen and R₂₈ is a phenylwhich is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a nitro, a hydroxyl, atrifluoromethyl, a (C₁-C₄)alkyl and a (C₁-C₄)alkoxy, said substituentsbeing identical or different; a pyridyl; or a pyrimidyl; or R₂₈ and R₂₉together form a divalent hydrocarbon group L₂, in which the 1-positionis bonded to the carbon atom carrying the substituent W₃, the divalenthydrocarbon group L₂ being selected from a trimethylene, acis-propenylene, a tetramethylene, a cis-butenylene, acis,cis-butadienylene, a pentamethylene and a cis-pentenylene, saiddivalent hydrocarbon group L₂ being unsubstituted or substituted by oneor two methyls; and R₃₁ and R₃₂ are each independently a hydrogen, a(C₁-C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₃₁ and R₃₂, together with thenitrogen atom to which they are bonded, form a heterocycle selected frompyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; iv—or a group B₄ of the formula

in which: W₄ is a (C₁-C₈)alkyl or a (C₃-C₈)cycloalkyl, said alkyl andcycloalkyl groups being unsubstituted or substituted by one or moresubstituents selected from a halogen atom; a (C₃-C₆)cycloalkyl; a cyano;a nitro; a hydroxyl; a (C₁-C₄)alkoxy; a formyloxy; a(C₁-C₄)alkylcarbonyloxy; an arylcarbonyl; a heteroarylcarbonyl; an oxo;an imino which is unsubstituted or substituted on the nitrogen atom by a(C₁-C₆)alkyl, a (C₃-C₆)cycloalkyl, a formyl, a (C₁-C₄)alkylcarbonyl oran arylcarbonyl; a hydroxyimino which is unsubstituted or substituted onthe oxygen atom by a (C₁-C₄)alkyl or a phenyl; a group —NR₃₃R₃₄containing from zero to seven carbon atoms; a group —NR₃₅R₃₆; a group—C(═NR₃₇)NR₃₈R₃₉, in which the group —NR₃₈R₃₉ contains from zero toseven carbon atoms; and a group —CON(OR₄₀)R₄₁, said substituents beingidentical or different; R₃₃ and R₃₄ are each independently a hydrogen, a(C₁-C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₃₃ and R₃₄, together with thenitrogen atom to which they are bonded, form a heterocycle selected frompyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; R₃₅ is a hydrogen or a (C₁-C₄)alkyl; R₃₆ is a formyl; a(C₁-C₄)alkylcarbonyl; an arylcarbonyl; a heteroarylcarbonyl; or a group—C(═W₅)NR₃₈R₃₉, in which the group —NR₃₈R₃₉ contains from zero to sevencarbon atoms; W₅ is an oxygen atom; a sulfur atom; a group NR₃₇; or agroup CHR₄₂; R₃₇ is a hydrogen or a (C₁-C₄)alkyl; or R₃₇ and R₃₉together form an ethylene group or a trimethylene group; R₃₈ and R₃₉ areeach independently a hydrogen, a (C₁-C₅)alkyl or a (C₃-C₆)cycloalkyl; orR₃₈ and R₃₉, together with the nitrogen atom to which they are bonded,form a heterocycle selected from pyrrolidine, piperidine, morpholine,thiomorpholine (or its S-oxide) and piperazine which is unsubstituted orsubstituted in the 4-position by a (C₁-C₄)alkyl; or R₃₈ is a hydrogen ora (C₁-C₄)alkyl and R₃₉ and R₃₇ together form an ethylene group or atrimethylene group; R₄₀ and R₄₁ are each independently a (C₁-C₃)alkyl;R₄₂ is a cyano; a nitro; or a group SO₂R₄₃; R₄₃ is a (C₁-C₄)alkyl or aphenyl; and when W₄ is a cyclic group or when a substituent of W₄ is acyclic group or contains a cyclic group, said cyclic groups can also besubstituted on a carbon atom by one or more (C₁-C₃)alkyls; and when asubstituent of W₄ contains an aryl group or a heteroaryl group, saidaryl or heteroaryl groups can also be monosubstituted or polysubstitutedby a substituent selected from a halogen atom, a (C₁-C₄)alkyl, a(C₁-C₄)alkoxy, a cyano, a trifluoromethyl and a nitro, said substituentsbeing identical or different; v—or a group B₅ of the formula

in which: W₆ and W₇ are each a hydrogen; or W₆ is a hydrogen and W₇ is ahydroxyl; W₈ is an aryl or a heteroaryl which are unsubstituted orsubstituted by an aryl, an arylcarbonyl, a heteroaryl or aheteroarylcarbonyl; said aryl or heteroaryl groups can also bemonosubstituted or polysubstituted on the aromatic or heteroaromaticmoiety and on a carbon atom by a substituent selected from a halogenatom; a cyano; a trifluoromethyl; a nitro; a hydroxyl; a (C₁-C₅)alkoxy;a formyloxy; a (C₁-C₄)alkylcarbonyloxy; a group —NR₃₃R₃₄ containing fromzero to seven carbon atoms; a group —NR₃₅R₃₆; a group —C(═NR₃₇)NR₃₈R₃₉,in which the group —NR₃₈R₃₉ contains from zero to seven carbon atoms; agroup —COOR₄₄; a group —CONR₄₅R₄₆, in which the group NR₄₅R₄₆ containsfrom zero to seven carbon atoms; a mercapto; a group —S(O)_(s)R₄₇; a(C₁-C₅)alkyl; a formyl; and a (C₁-C₄)alkylcarbonyl, said substituentsbeing identical or different; when W₆ and W₇ are each a hydrogen, W₈ isother than a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a nitro,a hydroxyl, a trifluoromethyl and a (C₁-C₄)alkoxy, said substituentsbeing identical or different; a pyridyl; a thienyl; a pyrimidyl; or animidazolyl which is unsubstituted or substituted by a (C₁-C₄)alkyl; orW₇ is a hydrogen and W₆ and W₈, together with a diradical W₉ and thepiperidine carbon atom to which they are bonded, form a spiro ring inwhich W₈ is a phenyl substituted in the ortho position by a diradicalW₉, which is itself joined to W₆, said phenyl being unsubstituted orsubstituted by a substituent selected from a halogen atom, a(C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a hydroxyl, a (C₁-C₃)alkylthio, a(C₁-C₃)alkylsulfinyl and a (C₁-C₃)alkylsulfonyl; the diradical W₉ is amethylene, a carbonyl or a sulfonyl; and W₆ is an oxygen atom or a group—NR₄₈—, in which R₄₈ is a hydrogen or a (C₁-C₃)alkyl; R₃₃, R₃₄, R₃₅,R₃₆, R₃₇, R₃₈ and R₃₉ are as defined above for the group B₄; R₄₄ is ahydrogen; a (C₁-C₅)alkyl; an aryl; a heteroaryl; an arylmethyl; or aheteroarylmethyl; R₄₅ and R₄₆ are each independently a hydrogen, a(C₁-C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₄₅ and R₄₆, together with thenitrogen atom to which they are bonded, form a heterocycle selected frompyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; s is zero, one or two; R₄₇ is a (C₁-C₆)alkyl; a(C₃-C₆)cycloalkyl; an aryl; or a heteroaryl; and when W₈ or asubstituent of W₈ contains a cyclic group, said cyclic group can also besubstituted by one or more methyls; and when a heteroaryl group formingpart of W₈ or of a substituent of W₈ contains a nitrogen atom as theheteroatom, said nitrogen atom can also be substituted by a(C₁-C₅)alkyl; and when W₈ or a substituent of W₈ contains a(C₁-C₅)alkyl, (C₁-C₅)alkoxy, formyl or (C₁-C₄)-alkylcarbonyl group, said(C₁-C₅)alkyl, (C₁-C₅)alkoxy, formyl or (C₁-C₄)alkyl-carbonyl groups canalso be substituted by a hydroxyl, a (C₁-C₃)alkoxy or one or morehalogen atoms, with the proviso that a carbon atom bonded to a nitrogenatom or to an oxygen atom is not substituted by a hydroxyl or an alkoxygroup, and with the proviso that a carbon atom in the α-position of a(C₁-C₄)alkylcarbonyl group is not substituted by a chlorine, bromine oriodine atom; vi—or a group B₆ of the formula

in which J₄ is: vi₁—either a group

in which: W₁₀ is a phenyl which is unsubstituted or monosubstituted totrisubstituted by a substituent selected from a halogen atom, a(C₁-C₆)alkoxy, a (C₁-C₆)alkyl and a trifluoromethyl, said substituentsbeing identical or different; a benzyl which is unsubstituted ormonosubstituted to trisubstituted by a substituent selected from ahalogen atom, a (C₁-C₆)alkoxy, a (C₁-C₆)alkyl and a trifluoromethyl,said substituents being identical or different; a naphthyl which isunsubstituted or monosubstituted to trisubstituted by a substituentselected from a halogen atom, a (C₁-C₆)alkoxy, a (C₁-C₆)alkyl and atrifluoromethyl, said substituents being identical or different; apyridyl which is unsubstituted or monosubstituted or disubstituted by asubstituent selected from a halogen atom, a (C₁-C₆)alkyl and a(C₁-C₆)alkoxy, said substituents being identical or different; athienyl; a pynmidyl; or an imidazotyl; and W₁₁ is a group —CONHR₄₉; R₄₉is a group CH₃—CHOH—CH—COO—(C₁-C₆) alkyl; a group(C₁-C₆)alkyl-OCO—CH₂—CH₂—CH—COO—(C₁-C₆) alkyl a group —CH₂CH₂N(CH₃)₂;

in which: R₅₀ is a hydrogen, a (C₁-C₆)alkyl or a benzyl; and R₅₁ is fromone to three substituents selected from a hydrogen, a halogen atom, atrifluoromethyl, a (C₁-C₆)alkyl and a (C₁-C₆)alkoxy, said substituentsbeing identical or different; vii—or a group B₇ of the formula

in which: f and g are each independently zero, one, two, three, four orfive, with the proviso that f+g is equal to one, two, three, four orfive; W₁₂ is a direct bond; a (C₁-C₃)alkylene which is unsubstituted orsubstituted by an oxo, a group OR₅₂, a halogen, a trifluoromethyl or aphenyl which is itself unsubstituted or mono-, di- or tri-substituted bya substituent selected from a hydroxyl, a cyano, a halogen and atrifluoromethyl; a group —S(O)_(k)—; a group (C₁-C₃)alkylene-S(O)_(k)-;a group —S(O)_(k)—(C₁-C₂)alkylene; a group —S(O)_(k)—NH—; a group—S(O)_(j)—NR₅₂—; a group —S(O)_(j)—NR₅₂—(C₁-C₂)alkylene; a group—CONR₅₂—; a group —CONR₅₂—(C₁-C₂)alkylene; a group —COO—; or a group—COO—(C₁-C₂)alkylene; W₁₃ is a group —NR₅₃—; an oxygen atom; a sulfuratom; a sulfinyl; or a sulfonyl, with the proviso that when W₁₂ is adirect bond and when W₁₄ is a (C₁-C₃)alkylene, W₁₃ is a group —NR₅₃—;W₁₄ is a direct bond; a (C₁-C₃)alkylene which is unsubstituted orsubstituted by an oxo, a group OR₅₂, a halogen, a trifluoromethyl or aphenyl which is itself unsubstituted or mono-, di- or tri-substituted bya substituent selected from a group OR₅₂, a halogen and atrifluoromethyl; a group —S(O)_(k)—; a group (C₁-C₃)alkylene-S(O)_(k)—;a group —S(O)_(k)—(C₁-C₂)alkylene; a group —NHS(O)_(j)—; a group—NH—(C₁-C₂)alkylene-S(O)_(j)—; a group —S(O)_(j)NR₅₂—; a group—S(O)_(j)—NR₅₂—(C₁-C₂)alkylene; a group —NHCO—(C₁-C₂)alkylene; a group—NR₅₂—CO—; a group —NR₅₂—(C₁-C₂)alkylene-CO—; a group —OCO—; or a group(C₁-C₂)alkylene-OCO—; W₁₅-W₁₆ together form two adjacent atoms of acyclic radical of the formula

said cyclic radical being a phenyl, a naphthyl or a heteroaryl groupselected from a benzimidazolyl, a benzofuranyl, a benzoxazolyl, afuranyl, an imidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, anoxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, apyrimidyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl, athiazolyl, a thienyl and a triazolyl, and said phenyl, naphthyl orheteroaryl cyclic radical being unsubstituted or mono-, di- ortri-substituted by R₅₄; k is zero, one or two; j is one or two; R₅₂ is ahydrogen; a (C₁-C₆)alkyl which is unsubstituted or monosubstituted ordisubstituted by a substituent selected independently from a hydroxyl,an oxo, a cyano, a halogen atom, a trifluoromethyl an d a phenyl whichis itself unsubstituted or substituted by a hydroxyl, a (C₁-C₃)alkyl, acyano, a halogen, a trifluoromethyl or a (C₁-C₄)alkoxy; a phenyl, apyridyl or a theophene, said phenyl, pyridyl or thiophene beingunsubstituted or mono-, di- or tri-substituted by a substituent selectedindependently from a hydroxyl, a (C₁-C₄)alkyl, a cyano, a halogen atomand a trifluoromethyl; or a (C₁-C₃)alkoxy; R₅₃ is a hydrogen; a(C₁-C₈)alkyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a group —OR₅₂, an oxo, agroup —NHCOR₅₂, a group —NR₅₅R₅₆, a cyano, a halogen atom, atrifluoromethyl and a phenyl which is itself unsubstituted orsubstituted by a hydroxyl, a cyano, a halogen atom or a trifluoromethyl;a group —S(O)R₅₇; a group —CO₂R₅₇; a group —SO₂R₅₇; a group —COR₅₇; or agroup —CONR₅₆R₅₇; R₅₄ is a hydrogen; a (C₁-C₆)alkyl which isunsubstituted or monosubstituted or disubstituted by a hydrogen or ahydroxyl; an oxo; a group —OR₅₂; a halogen atom; a trifluoromethyl; anitro; a cyano; a group —NR₅₅R₅₆; a group —NR₅₅COR₅₆; a group—NR₅₅CO₂R₅₆; a group —NHS(O)_(j)R₅₂; a group —NR₅₅S(O)_(j)R₅₆; a group—CONR₅₅R₅₆; a group —COR₅₂; a group —CO₂R₅₂; a group —S(O)_(j)R₅₅ ₂; ora heteroaryl group, said heteroaryl being selected from abenzimidazolyl, a benzofuranyl, a benzoxazolyl, a firanyl, animidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl,an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidinyl, apyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl, a thiazolyl, athienyl and a triazolyl, and said heteroaryl being unsubstituted ormonosubstituted or disubstituted by R₅₈; R₅₅ is R₅₂; R₅₆ is R₅₂; or R₅₅and R₅₆, together with the atoms to which they are bonded, form a five-,six- or seven-membered, saturated monocyclic heterocycle containing oneor two heteroatoms, said heteroatoms being selected independently from anitrogen atom, an oxygen atom and a sulfur atom, said heterocycle beingunsubstituted or monosubstituted or disubstituted by a substituentselected from a hydroxyl, an oxo, a cyano, a halogen atom and atrifluoromethyl; R₅₇ is a (C₁-C₆)alkyl which is unsubstituted or mono-,di- or tri-substituted by a substituent selected from a hydroxyl, anoxo, a cyano, a group —OR₅₂, a group —NR₅₅R₅₆, a group —NR₅₅COR₅₆, ahalogen atom, a trifluoromethyl and a phenyl which is itselfunsubstituted or mono-, di- or tri-substituted by a substituent selectedfrom a hydroxyl, an oxo, a cyano, a group —NHR₅₂, a group —NR₅₅R₅₆, agroup —NR₅₅COR₅₆, a halogen atom, a trifluoromethyl and a (C₁-C₃)alkyl;R₅₈ is a hydrogen; a (C₁-C₆)alkyl which is unsubstituted ormonosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; agroup —OR₅₂; a trifluoromethyl; a nitro; a cyano; a group —NR₅₅R₅₆; agroup —NR₅₅COR₅₆; a group —NR₅₅CO₂R₅₆; a group —NHS(O)_(j)R₅₂; a group—NR₅₅S(O)_(j)R₅₆; a group —CONR₅₅R₅₆; a group —COR₅₂; a group —CO₂R₅₂; agroup —S(O)_(j)R₅₂; or a phenyl, and the group B₇ being other than thegroup B₅ when W₇ is a hydrogen and W₆ and W₈, together with a diradicalW₉ and the piperidine carbon atom to which they are bonded, form a spiroring; viii—or a group B₈ of the formula

in which: W₁₇ is a direct bond; a double bond; or a divalent hydrocarbonradical; W₁₈ is a radical which is joined to the carbon atom of theheterocycle either by a single bond when W₁₇ is a double bond, or by adouble bond in the other cases; W₁₉ is an unsubstituted or optionallysubstituted heteroatom; W₂₀ is a hydrocarbon radical of which the1-position is joined to W₁₉; and the meanings of W₁₇, W₁₈, W₁₉ and W₂₀are selected from: (a) W₁₇ is a direct bond; W₁₈ is an oxo or thioxogroup; W₁₉ is an oxy or thio group or a group NR₅₉; and W₂₀ is ahydrocarbon radical L₃; or (b) W₁₇ is a direct bond; W₁₈ is a groupNR₆₀; W₁₉ is a group NR₆₁; and W₂₀ is a hydrocarbon radical L₃; or (c)W₁₇ is a double bond; W₁₈ is a group OR₆₁, SR₆₁ or NR₆₂R₆₃; W₁₉ is anitrogen atom; and W₂₀ is a hydrocarbon radical L₃; or (d) W₁₇ is amethylene which is unsubstituted or substituted by one or two methylgroups; W₁₈ is an oxo or thioxo group or a group NR₆₄; W₁₉ is an oxy,thio, sulfinyl or sulfonyl group or a group NR₆₁; and W₂₀ is ahydrocarbon radical L₄; or (e) W₁₇ is a direct bond; W₁₈ is an oxo orthioxo group or a group NR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is ahydrocarbon radical L₅; or (f) W₁₇ is a methine group which isunsubstituted or substituted by one or two methyl groups; W₁₈ is an oxoor thioxo group or a group NR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is ahydrocarbon radical L₆; and (g) W₁₇ is a cis-vinylene group which isunsubstituted or substituted by one or two methyl groups; W₁₈ is an oxoor thioxo group or a group NR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is ahydrocarbon radical L₇; R₅₉ is a hydrogen; a (C₁-C₃)alkyl; a group—CH₂COOR₆₅; or a group —CH₂CONR₆₆R₆₇; R₆₀ is a hydrogen; a (C₁-C₃)alkyl;a cyano; a nitro; or a (C₁-C₃)alkylsulfonyl group; R₆₁ is a hydrogen ora (C₁-C₃)alkyl; R₆₂ and R₆₃ are each independently a hydrogen or a(C₁-C₃)alkyl; or R₆₂ and R₆₃, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; R₆₄ is a hydrogen or a (C₁-C₃)alkyl; R₆₅ is a hydrogen ora (C₁-C₃)alkyl; R₆₆ and R₆₇ are each independently a hydrogen; a(C₁-C₃)alkyl; a phenyl; or a benzyl; L₃ is an ethylene, a cis-vinylene,a trimethylene or a tetramethylene, said hydrocarbon radical L₃ beingunsubstituted or substituted by one or two methyl groups; L₄ is anethylene or a trimethylene, said hydrocarbon radical L₄ beingunsubstituted or substituted by one or two methyl groups; L₅ is aprop-2-en-1-yliden-3-yl which is unsubstituted or substituted by one ortwo methyl groups; L₆ is a cis-vinylene which is unsubstituted orsubstituted by one or two methyl groups; and L₇ is a methine which isunsubstituted or substituted by a (C₁-C₃)alkyl; ix—or a group B₉ of theformula

in which J₅ is: a group

in which: X₂ is a (C₁-C₆)alkyl; a group —CH₂—OR₆₈; a group —CH₂—SR₆₈; agroup —CH₂—S(O)R₆₉; a group —CH₂—SO₂R₆₉; a group —COOR₆₈; a group—C(═W₂₄)NR₇₀R₇₁; a group —C(R₆₈)(OR₇₂)(OR₇₃); a group—CH₂NR₆₈C(═W₂₄)R₇₄; a group —CH₂—NR₆₈COOR₇₄; or a group—CH₂NR₆₈C(═W₂₄)NR₇₀R₇₁; W₂₁ is a direct bond and W₂₂ is a hydrocarbonradical of which the 1-position is joined to W₂₁, the hydrocarbonradical W₂₂ being selected from a trimethylene, a tetramethylene, acis-1-butenylene and a cis,cis-butadienylene; or W₂₁ is a group NR₇₅ andW₂₂ is a hydrocarbon radical selected from an ethylene, a trimethyleneand a cis-vinylene; or W₂₁ is a nitrogen atom and W₂₂ is acis,cis-prop-2-en-1-yliden-3-yl radical of which the 1-position isjoined to W₂₁; W₂₃ is an oxygen atom or a sulfur atom; W₂₄ is an oxygenatom or a sulfur atom; R₆₈ is a hydrogen or a (C₁-C₆)alkyl; R₆₉ is a(C₁-C₆)alkyl; R₇₀ and R₇₁ are each independently a hydrogen; a(C₁-C₆)alkyl which is unsubstituted or substituted by a hydroxyl or a(C₁-C₃)alkoxy; an ω—HO—(C₁-C₆)alkyl; an ω-(C₁-C₃)alkoxy-(C₁-C₆)alkyl; anω-phenyl-(C₁-C₆)alkyl; an ω—R₇₆OOC—(C₁-C₆)alkyl; or anω—R₇₇R₇₈NCO—(C₁-C₆)alkyl; or R₇₀ and R₇₁, together with the nitrogenatom to which they are bonded, form a heterocycle selected frompyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) andpiperazine which is unsubstituted or substituted in the 4-position by amethyl group or an ethyl group; R₇₂ and R₇₃ are each independently a(C₁-C₃)alkyl; or R₇₂ and R₇₃ together form a divalent hydrocarbonradical selected from an ethylene and a trimethylene; R₇₄ is a hydrogenor a (C₁-C₆)alkyl; R₇₅ is a hydrogen or a (C₁-C₆)alkyl; R₇₆ is ahydrogen or a (C₁-C₃)alkyl; and R₇₇ and R₇₈ are each independently ahydrogen or a (C₁-C₃)alkyl; x—or a group B₁₀ of the formula

in which J₆ is:

in which: X₁ is as defined above for the group B₁, X₁ being other thanhydrogen when W₂₅ is a (C₁-C₇)alkyl or a (C₃-C₇)cycloalkyl; W₂₅ is a(C₁-C₇)alkyl or a (C₃-C₇)cycloalkyl; W₂₅ can also be a group —NR₇₉R₈₀when X₁ is a hydrogen, a cyano, a carboxyl, a (C₁-C₇)alkoxycarbonyl or agroup —CONR₁₉R₂₀; and R₇₉ and R₈₀ are each independently a (C₁-C₇)alkyl;or R₇₉ and R₈₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine and perhydroazepine, with theproviso that: 1/ when simultaneously: R₂ is a methyl group or R₁ and R₂together form a group —(CH₂)₃—; Ar₁ is a 3,4-dichlorophenyl; T is agroup —CH₂—; a group —CO—; a group —COO—; or a group —CONR₃; A is adirect bond; a group —(CH₂)_(t)— in which t is one, two or three; or avinylene group; or —T—A— is the group —SO₂—; and Z is a phenyl which isunsubstituted or monosubstituted or polysubstituted by a halogen, a(C₁-C₄)alkyl, a (C₁-C₄)alkoxy or a nitro, B is a group B of the formula

in which J₁ is a group

in which: x is zero; Ar₂ is a pyrid-2-yl or a phenyl which isunsubstituted or substituted by a halogen, a methyl or a (C₁-C₄)alkoxy;and X₁ is otherthan a group selected from: formyl; (C₁-C₆)alkylcarbonyl;—(CH₂)_(m)—OR₄ in which m is zero or one and R₄ is a hydrogen or a(C₁-C₇)alkyl; —(CH₂)_(m)—OCOR₅ in which m is zero or one and R₅ is ahydrogen or a (C₁-C₆)alkyl; —(CH₂)_(m)—OCONH(C₁-C₇)alkyl in which m isone; —NR₈R₉ in which R₈ and R₉ are each independently a hydrogen or a(C₁-C₇)alkyl; R₉ can also be a (C₃-C₇)cycloalkylmethyl, a benzyl or aphenyl; or R₈ and R₉, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine and perhydroazepine;—(CH₂)_(p)—NR₁₀R₁₁ in which p is one and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a(C₁-C₇)cycloalkylmethyl or a benzyl; —NR₁₂COR₁₃ in which R₁₂ is ahydrogen or a (C₁-C₄)alkyl and R₁₃ is a hydrogen, a (C₁-C₇)alkyl, aphenyl, a benzyl, a pyridyl or a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; or R₁₂ and R₁₃together are a group —(CH₂)_(u)— in which u is three or four;—(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom, R₁₄ isa hydrogen or a (C₁-C₄)alkyl and R₁₆ is a hydrogen, a (C₁-C₇)alkyl, aphenyl, a benzyl, a pyridyl or a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls;—(CH₂)_(m)—NR₁₄COOR₁₇ in which m is zero or one, R₁₄ is a hydrogen or a(C₁-C₄)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl;—(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is zero or one, R₁₄ is a hydrogen or a(C₁-C₄)alkyl and R₁₈ is a (C₁-C₇)alkyl, an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a(C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, said substituents beingidentical or different; —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is zeroor one, W₁ is an oxygen atom, R₁₄ is a hydrogen or a (C₁-C₄)alkyl andR₁₉ and R₂₀ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₀ canalso be a (C₃-C₇)cycloalkyl, a (C₃-C₇)-cycloalkylrmethyl, a hydroxyl, a(C₁-C₄)alkoxy, a benzyl or a phenyl; or R₁₉ and R₂₀, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine andperhydroazepine; —(CH₂)_(n)—COOR₂₁ in which n is zero and R₂₁ is a(C₁-C₇)alkyl; —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is zero, W₁ is anoxygen atom and R₁₉ and R₂₀ are as defined above; and —CN; or X₁ doesnot form a double bond between the carbon atom to which it is bonded andthe adjacent carbon atom of the piperidine ring; or Ar₂ and X₁, togetherwith the carbon atom to which they are bonded, are other than a group ofthe formula

2/ when R₁ is hydrogen, R₂ is the methyl group, Ar₁ is the3,4-dichlorophenyl group and T—A—Z is the thenoyl group, B is the groupB₁ in which J₁ is the group

in which x is one, Ar₂ is the phenyl group and X₁ is other thanhydrogen; 3/ when R₁ is hydrogen, R₂ is the methyl group, Ar₁ is the3,4-dichlorophenyl group and T—A—Z is the 2,4-dichlorobenzoyl group, Bis the group B₁ in which J₁ is the group

in which x is one, Ar₂ is the phenyl group and X₁ is other thanhydrogen; or 4/ when R₁ and R₂ together form a group —(CH₂)₃—, Ar₁ isthe 3,4-dichlorophenyl group and T—A—Z is the 2-(3-methoxyphenyl)acetylgroup, B is the group B₁ in which J₁ is the group

in which x is, one, Ar₂ is phenyl and X₁ is other than hydrogen; and itssalts, where appropriate, with mineral or organic acids.
 2. A compoundof formula (I) according to claim 1 in which: Z is Z′ and is: a phenylwhich is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom; a trifluoromethyl; a cyano; ahydroxyl; a nitro; an amino which is unsubstituted or monosubstituted ordisubstituted by a (C₁-C₄)alkyl; a benzylamino; a carboxyl; a(C₁-C₁₀)alkyl; a (C₃-C₈)cycloalkyl which is unsubstituted ormonosubstituted or polysubstituted by a methyl; a (C₁-C₁₀)alkoxy; a(C₃-C₈)cycloalkoxy which is unsubstituted or monosubstituted orpolysubstituted by a methyl; a mercapto; a (C₁-C₁₀)alkylthio; aformyloxy; a (C₁-C₆)alkylcarbonyloxy; a formylamino; a(C₁-C₆)alkylcarbonylamino; a benzoylamino; a (C₁-C₄)alkoxycarbonyl; a(C₃-C₇)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted ormonosubstituted or disubstituted by a (C₁-C₄)alkyl; a ureido which isunsubstituted or monosubstituted or disubstituted in the 3-position by a(C₁-C₄)alkyl or a (C₃-C₇)cycloalkyl; and a(pyrrolidin-1-yl)-carbonylamino, said substituents being identical ordifferent; a naphthyl which is unsubstituted or monosubstituted orpolysubstituted by a halogen, a trifluoromethyl, a (C₁-C₄)alkyl, ahydroxyl or a (C₁-C₄)alkoxy; or a pyridyl; a thienyl; an indolyl; aquinolyl; a benzothienyl; or an imidazolyl; Ar₁ is a 3,4-dichlorophenyl;R₁ and R₂ together fonn a group —(CH₂)₃— or —(CH₂)₄—; and B, T and A areas defined for (I) in claim 1, and its salts with mineral or organicacids.
 3. A compound of formula (I) according to claim 1 in which: Z isZ^(•) and is a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl,benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzisothiazolyl, quinolyt, isoquinolyl, benzoxazolyl,benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl,thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl,pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl orchromanyl group, in which one or more double bonds can be hydrogenated,it being possible for said groups to be unsubstituted or optionally tocontain one or more substituents such as an alkyl, phenyl, cyano,hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkylgroup, in which the alkyl and alkoxy groups are C₁-C₄; R₁ and R₂together form a group —(CH₂)₃—; Ar₁ is a 3,4-dichlorophenyl; T is agroup —CO—; A is a direct bond; and B is as defined for a compound offormula (I) in claim 1, and its salts with mineral or organic acids. 4.A compound of the formula according to one of claims 1 or 3 of theformula

in which: Z^(•) is as defined in claim 3; and B^(•) is a group of theformula

in which J^(•) is: i^(•)—either a group of the structure

in which: W^(•) is a phenyl or a benzyl and R₁₉ and R₂₀ are as definedfor a compound of formula (I) in claim 1; or W^(•) is a group —NR₇₉R₈₀in which R₇₉ and R₈₀ are as defined for (I) in claim 1 and R₁₉ and R₂₀are each hydrogen; i^(••)—or a group of the structure

in which: R^(•) is hydrogen, a methyl group, an acetyl group, amethoxycarbonyl group, a dimethylaminocarbonyl group or amethanesulfonyl group, and its salts with mineral or organic acids.
 5. Acompound according to one of claims 1, 3 or 4 of the formula

in which: B^(•) is as defined for a compound of formula (I^(•)) in claim4; and Z^(••) is a pyridyl, for example a 4-pyridyl, a 2-thienyl, a3-thienyl, a 2-furyl or a 3-furyl, and its salts with mineral or organicacids.
 6. A compound according to one of claims 1, 3, 4 or 5 of theformula

in which: Z^(••) is as defined in claim 5, and its salts with mineraland organic acids.
 7. A compound according to claim 1 or claim 2 offormula (I) in which simultaneously: B is a group B₃ in which: either W₃is oxygen, R₂₉ is a (C₁-C₄)alkyl or a trifluoromethyl and R₂₈ is a(C₁-C₆)alkyl, especially an ethyl; or W₃ is oxygen, R₂₈ is an allyl or acyclohexyl and R₂₉ is a methyl; or W₃ is oxygen, R₂₈ is an ethyl and R₂₉is a methylamino or a dimethylamino; or W₃ is oxygen and R₂₈ and R₂₉together form a 1,3-propylene, 1,4-butylene or cis,cis-1,4-butadienylgroup; or W₃ is sulfur and R₂₈ and R₂₉ together form a 1,4-butylenegroup; R₁ and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—; Ar₁ is a3,4-dichlorophenyl; Z═Z′ as defined in claim 2; and T and A are asdefined above for a compound of formula (I) in claim 1, and its saltswith mineral or organic acids.
 8. A compound according to claim 1 orclaim 2 of formula (I) in which simultaneously: B is B₄ in which: W₄ is1-hydroxypropyl, 1-hydroxyethyl, 1-hydroxybutyl, 2-hydroxybut-2-yl,4-hydroxyhept-4-yl, 2-hydroxyethyl, 1-hydroxyiminopropyl (syn or anti),1-methoxyiminopropyl (syn or anti), 2-acetoxyethyl, 2-acetamidoethyl,carboxyl, ethoxycarbonyl or pyrrolidin-1-ylcarbonyl; R₁ and R₂ togetherform a group —(CH₂)₃— or —(CH₂)₄—; Ar₁ is a 3,4-dichlorophenyl; Z═Z′ asdefined in claim 2; and T and A are as defined above for a compound offormula (I) in claim 1, and its salts with mineral or organic acids. 9.A compound according to claim 1 or claim 2 of formula (I) in whichsimultaneously: B is a group B₅ in which: W₇ is a hydroxyl, W₆ is ahydrogen and W₉ is a phenyl; or W₆ and W₇ are hydrogen and W₈ isselected from the following groups: 5-methyl-1,3,4-oxadiazol-2-yl,4-ethoxycarbonylimidazol-2-yl, 2-fluoropyrid-3-yl, 2-methylthiophenyl,4-methylthiophenyl, 2-methylsulfinylphenyl, 4-methylsulfinylphenyl and4-(N-methylcarbamoyl)phenyl; or W₇ is hydrogen and W₆ and W₈, togetherwith the piperidine to which they are bonded, form aspiro[isobenzofuran-1(3H),4′-piperid]-1′-yl group or a3-oxospiro[isobenzofuran-1(3H),4′-piperid]-1′-yl group; R₁ and R₂together form a group —(CH₂)₃— or —(CH₂)₄—; Ar₁ is a 3,4-dichlorophenyl;Z═Z′ as defined in claim 2; and T and A are as defined above for acompound of formula (I) in claim 1, and its salts with mineral ororganic acids.
 10. A compound according to claim 1 or claim 2 of formula(I) in which simultaneously: B is a group B₆ as defined in claim 1; R₁and R₂ together form a group —(CH₂)₃— or —(CH₂)₄—; Ar₁ is a3,4-dichlorophenyl; Z═Z′ as defined in claim 2; and T and A are asdefined above for a compound of formula (I) in claim 1, and its saltswith mineral or organic acids.
 11. A compound according to claim 1 orclaim 2 of formula (I) in which simultaneously: B is a group B₇ selectedfrom: a) a 1-methanesulfonyl-spiro(indoline-3,4′-piperid-1′-yl) b) a1-benzyloxycarbonyl-spiro(indoline-3,4′-piperid-1′-yl) c) aspiro(indoline-3,4′-piperid-1′-yl) d) a1-acetyl-spiro(indoline-3,4′-piperid-1′-yl) e) a1-propionyl-spiro(indoline-3,4′-piperid-1′-yl) f) a1-formyl-spiro(indoline-3,4′-piperid-1′-yl) g) a1-tert-butylcarbonyl-spiro(indoline-3,4′-piperid-1′-yl) h) a1-methylaminocarbonyl-spiro(indoline-3,4′piperid-yl) i) a1-ethoxycarbonyl-spiro(indoline-3,4′-piperid-1′-yl) j) a1-ethanesulfonyl-spiro(indoline-3,4′-piperid-1′-yl) k) a1-isopropanesulfonyl-spiro(indoline-3,4′-piperid-1′-yl) l) a1′-methyl-1-methanesulfonyl-spiro(indoline-3,4′-piperidinio-1′) iodidem) a 1-(2-aminoacetyl)-spiro(indoline-3,4′-piperid-1′-yl) n) a1′-methyl-spiro(indol-2-one-3,4′-piperid-1′-yl) o) a2-methyl-spiro(isoindol-1-one-3,4′-piperid-1′-yl) p) aspiro(2-oxotetrahydroquinoline-4-4′-piperid-1′-yl) q) a1-methyl-spiro(2-oxotetrahydro quinoline-4,4′-piperid-1′-yl) r) aspiro(2,3-dihydrobenzothiophene-3,4′-piperid-1′-yl) s) a5-fluoro-spiro(2,3-dihydrobenzofuran-3,4′-piperid-1′-yl) t) aspiro(2,3-dihydrobenzofuran-3,4′-piperid-4′-yl) u) aspiro(2,3-dihydrobenzothiophene-3,4′-piperid-1′-yl)1-oxide v) aspiro(2,3-dihydrobenzothiophene-3,4′-piperid-1′-yl)1,1-dioxide w) a5-fluoro-1-methanesulfonyl-spiro(indoline-3,4′-piperid-1′-yl) x) a1-methanesulfonyl-5-methoxy-spiro(indoline-3,4′-piperid-1-yl) y) a1-methanesulfonyd-5-methyl-spiro(indoline-3,4′-piperid-1′-yl) z) a5-chloro-1-methanesulfonyl-spiro(indoline-3,4′-piperid-1′-yl) aa) a7-fluoro-1-methanesulfonyl-spiro(indoline-3,4′-piperid-1′-yl) ab) a1-acetyl-5-fluoro-spiro(indoline-3,4′-piperid-1-yl) ac) a1-acetyl-5-chloro-spiro(indoline-3,4′-piperid-1′-yl) ad) a1-acetyl-5-methyl-spiro(indoline-3,4′-piperid-1′-yl) ae) a1-acetyl-6-fluoro-spiro(indoline-3,4′-piperid-1′-yl) af) a1-acetyl-4-fluoro-spiro(indoline-3,4′-piperid-1′-yl) ag) a1-(N,N-dimethylcarbamoyl)-spiro(indoline-3,4′-piperid-1′-yl); R₁ and R₂together form a group —(CH₂)₃— or —(CH₂)₄—; Ar₁ is a 3,4-dichlorophenyl;Z═Z′ as defined in claim 2; and T and A are as defined above for (I) inclaim 1, and its salts with mineral or organic acids.
 12. A compoundaccording to claim 1 or claim 2 of formula (I) in which simultaneously:B is a group B₈ in which: W₁₇ is a direct bond, W₁₈ is an oxo or thioxogroup, W₁₉ is an oxy group or a group NH and W₂₀ is an ethylene ortrimethylene group; R₁ and R₂ together form a group —(CH₂)₃ or —(CH₂)₄—;Ar₁ is a 3,4-dichlorophenyl; Z═Z′ as defined according to claim 2; and Tand A are as defined above for (I) for claim 1, and its salts withmineral or organic acids.
 13. A compound according to claim 1 or claim 2of formula (I) in which simultaneously: B is a group B₉ in which: X₂ isa group —COOR₆₈ or a group —C(═W₂₄)NR₇₀R₇₁ and W₂₁, W₂₂ and W₂₃,together with the nitrogen atom, form a 2-oxopiperidino group or a2-oxoperhydropyrimidin-1-yl group; R₁ and R₂ together form a group—(CH₂)₃— or —(CH₂)₄—; Ar₁ is a 3,4-dichlorophenyl; Z═Z′ as defined inclaim 2; and T and A are as defined above for (I) in claim 1, and itssalts with mineral or organic acids.
 14. A compound according to claim 1or claim 2 of formula (I) in which simultaneously: B is a group B₁₀ asdefined in claim 1; R₁ and R₂ together form a group —(CH₂)₃— or—(CH₂)₄—; Ar₁ is a 3,4-dichlorophenyl; Z═Z′ as defined in claim 2; and Tand A are as defined above for (I) in claim 1, and its salts withmineral or organic acids.
 15. A compound according to claim 1, 2 or 14of formula (I) in which simultaneously: B is a group B₁₀ in which J₆ isa group

in which: W₂₅ is a piperid-1-yl and X₁ is a hydrogen, or W₂₅ is anazetidin-1-yl, a pyrrolidin-1-yl, a piperid-1-yl, a morpholin-4-yl, athiomorpholin-4-yl or a perhydroazepin-1-yl and X₁ is a carbamoyl; R₁and R₂ together form a group —(CH₂)₃—; Ar₁ is a 3,4-dichlorophenyl; Z═Z′as defined in claim 2; T is a group —CO—; and A is a direct bond, andits salts with mineral or organic acids.
 16. A compound according to oneof claims 1 or 2 of the formula

in which: Ar′₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; A′ is adirect bond or a group —CH₂—; Z′ is as defined in claim 2; and B_(a) isa group B_(1a) of the formula

in which J_(1a) is a group in which: x is zero; Ar_(2a) is a phenylwhich is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a(C₁-C₄)alkyl, a trifluoromethyl and a methylenedioxy, said substituentsbeing identical or different; and X_(1a) is a group selected from:hydrogen; (C₁-C₇)alkyl; —(CH₂)_(m)—OR₄ in which m is two and R₄ is ahydrogen or a (C₁-C₇)alkyl; —(CH₂)_(m)—OCOR₅ in which: m is two and R₅is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; or apyridyl; or m is zero or one and R₅ is a (C₃-C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; or apyridyl; —(CH₂)_(m)—OCONH(C₁-C₇)alkyl in which m is zero or two;—O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl; —(CH₂)_(n)—SR₇ in which n is zero or one and R₇ isa hydrogen or a (C₁-C₇)alkyl; —CH₂—S(O)_(j)—(C₁-C₇)alkyl in which j isone or two; —NR₈R₉ in which R₈and R₉, together with the nitrogen atom towhich they are bonded, form a piperazine heterocycle which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;—(CH₂)_(p)—NR₁₀R₁₁ in which p is two and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁-C₇)atkyl; R₁₁ can also be a(C₃-C₇)cycloalkylmethyl or a benzyl; —NR₁₂COR₁₃ in which R₁₂ is ahydrogen or a (C₁-C₇)alkyl and R₁₃ is a vinyl, a furyl, a thienyl, apyrrolyl or an imidazolyl; —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a(C₁-C₇)alkyl and R₁₅ is a (C₁-C₄)alkoxy; —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ inwhich p is two, W₁ is an oxygen atom or a sulfur atom, R₁₄ is a hydrogenor a (C₁-C₇)alkyl and R₁₆ is a hydrogen; a (C₁-C₇)alkyl; a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; apyrrolyl; or an imidazolyl; and p is one, W₁ is a sulfur atom and R₁₄and R₁₆ are as just defined, or W₁ is an oxygen atom, R₁₄ is as justdefined and R₁₆ is a vinyl, a furyl, a thienyl, a pyrrolyl or animidazolyl; —(CH₂)_(m)—NR₁₄COOR₁₇ in which m is two, R₁₄ is a hydrogenor a (C₁-C₇)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl;—(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is two, R₁₄ is a hydrogen or a(C₁-C₇)alkyl and R₁₈ is a (C₁-C₇)alkyl; an amino which is free orsubstituted by one or two (C₁-C₇)alkyls; or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkylcarbonyloxy, acyano, a nitro and an amino which is free or substituted by one or two(C₁-C₇)alkyls, said substituents being identical or different;—(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is two, W₁ is an oxygen atom ora sulfur atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₉ and R₂₀ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₀ can also be a(C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a(C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; and m is zero or one, W₁ is a sulfur atom and R₁₄, R₁₉ andR₂₀ are as just defined, or W₁ is an oxygen atom, R₁₄ and R₁₉ are eachindependently a hydrogen or a (C₁-C₇)alkyl and R₂₀ is a (C₁-C₇)alkylsubstituted by a hydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a(C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted orsubstituted by one or two (C₁-C₇)alkyls; or R₁₉ and R₂₀, together withthe nitrogen atom to which they are bonded, form a piperazineheterocycle which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; —(CH₂)_(n)—COOR₂₁ in which n is one and R₂₁ is a hydrogenor a (C₁-C₇)alkyl; and n is zero and R₂₁ is a hydrogen;—(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is one, W₁ is an oxygen atom or asulfur atom and R₁₉ and R₂₀ are each independently a hydrogen or a(C₁-C₇)alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; aphenyl; or a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, aphenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁-C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl; and nis zero, W₁ is a sulfur atom and R₁₉ and R₂₀ are as just defined, or W₁is an oxygen atom, R₁₉ is a hydrogen or a (C₁-C₇)alkyl and R₂₀ is a(C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)atkoxy, a phenyl, acarboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstitutedor substituted by one or two (C₁-C₇)alkyls; or R₁₉ and R₂₀, togetherwith the nitrogen atom to which they are bonded, form a piperazineheterocycle which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; —CO—NR₂₂NR₂₃R₂₄ in which R₂₂ is a hydrogen or a(C₁-C₇)alkyl and R₂₃ and R₂₄ are each independently a hydrogen or a(C₁-C₇)alkyl;

in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be a formyl ora (C₁-C₇)alkylcarbonyl; and

and its salts with mineral or organic acids.
 17. A compound according toany one of claims 1, 2 or 16 of the formula

in which: B′_(a) is a group B′_(1a) of the formula

in which J′_(1a) is a group

in which: x is zero; Ar_(2a) is as defined for a compound of formula(Ia) in claim 16; and X′_(1a) is a group selected from: —O—CH₂—CH₂—OR₆in which R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl; —NR₁₂COR₁₃ in which R₁₂ is a hydrogen or a(C₁-C₇)alkyl and R₁₃ is a vinyl, a furyl, a thienyl, a pyrrolyl or animidazolyl; NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl andR₁₅ is a (C₁-C₄)alkoxy; —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one, W₁is an oxygen atom, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₆ is avinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;—(CH₂)_(p)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is zero, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁-C₇)alkyl, R₁₉ is a hydrogen or a (C₁-C₇)alkyland R₂₀ is a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, aphenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁-C₇)alkyls;—CO—NR₂₂—NR₂₃R₂₄ in which R₂₂ is a hydrogen or a (C₁-C₇)alkyl and R₂₃and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be a formyl ora (C₁-C₇)alkylcarbonyl; and

and its salts with mineral or organic acids.
 18. A compound according toany one of claims 1, 2, 16 or 17 of the formula

in which: X″_(1a) is a group selected from: —O—CH₂—CH₂—OR₆ in which R₆is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a (C₁-C₇)alkylcarbonyl,preferably a hydrogen or an acetyl; —NR₁₂COR₁₃ in which R₁₂ is ahydrogen or a (C₁-C₇)alkyl, preferably a hydrogen, and R₁₃ is a vinyl, afuryl, a thienyl, a pyrrolyl or an imidazolyl, preferably a furyl or athienyl; NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl,preferably a hydrogen, and R₁₅ is a (C₁-C₄)alkoxy, preferably an ethoxy;and

in which R₂₅ is a hydrogen or a (C₁-C₇)akyl, preferably a hydrogen, andR₂₆ and R₂₇ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ canalso be a formyl or a (C₁-C₇)alkylcarbonyl; R₂₆ and R₂₇ are preferably ahydrogen; and

and its salts with mineral or organic acids.
 19. A compound according toclaim 1 or claim 2 of the formula

in which: Ar′₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; A′ is adirect bond or a group —CH₂—; Z′ is as defined in claim 2; and B_(b) isa group B_(1b) of the formula

in which J_(1b) is a group

in which: x is one; Ar_(2a) is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, atrifluoromethyl and a methylenedioxy, said substituents being identicalor different; and X_(1b) is a group selected from: hydrogen;(C₁-C₇)alkyl; formyl; (C₁-C₇)alkylcarbonyl; —(CH₂)_(m)—OR₄;—(CH₂)_(m)—OCOR₅; —(CH₂)_(m)—OCONH—(C₁-C₇)alkyl; —O—CH₂CH₂—OR₆;—(CH₂)_(n)—SR₇; —CH₂—S(O)_(j)—(C₁-C₇)alkyl; —NR₈R₉; —(CH₂)_(p)—NR₁₀R₁₁;—NR₁₂COR₁₃; —NR₁₄COCOR₁₅; —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆;—(CH₂)_(m)—NR₁₄COOR₁₇; —(CH₂)_(m)—NR₁₄SO₂R₁₈;—(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀; —(CH₂)_(n)—COOR₂₁;—(CH₂)_(n)—C(═W₁)NR₁₉R₂₀; —CO—NR₂₂—NR₂₃R₂₄;

 or X_(1b) forms a double bond between the carbon atom to which it isbonded and the adjacent carbon atom of the piperidine ring, in whichgroups: m is zero, one or two; n is zero or one; p is one or two; j isone or two; W₁ is an oxygen atom or a sulfur atom; R₄ is a hydrogen or a(C₁-C₇)alkyl; R₅ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;or a pyridyl; R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl; R₇ is a hydrogen or a (C₁-C₇)alkyl; R₈ and R₉ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₉ can also be a(C₃-C₇)cycloalkylmethyl, a benzyl or a phenyl; or R₈ and R₉, togetherwith the nitrogen atom to which they are bonded, form a heterocycleselected from azetidine, pyrrolidine, piperidine, morpholine,thiomorpholine, perhydroazepine and piperazine which is unsubstituted orsubstituted in the 4-position by a (C₁-C₄)alkyl; R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a(C₃-C₇)cycloalkylmethyl or a benzyl; R₁₂ is a hydrogen or a(C₁-C₇)alkyl; R₁₃ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or animidazolyl; or R₁₂ and R₁₃ together are a group —(CH₂)_(u)— in which uis three or four; —R₁₄ is a hydrogen or a (C₁-C₇)alkyl; R₁₅ is a(C₁-C₄)alkoxy; R₁₆ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or animidazolyl; R₁₇ is a (C₁-C₇)alkyl or a phenyl; R₁₈ is a (C₁-C₇)alkyl; anamino which is free or substituted by one or two (C₁-C₇)alkyls; or aphenyl which is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a (C₁-C₇)alkyl, atrifluoromethyl, a hydroxyl, a(C₁-C₇)alkoxy, a carboxyl, a(C₁-C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro andan amino which is free or substituted by one or two (C₁-C₇)alkyls, saidsubstituents being identical or different; R₁₉ and R₂₀ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₂₀ can also be a(C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a(C₁-C₄)alkoxy; a benzyl; a phenyl, or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; R₂₁ is a hydrogen or a (C₁-C₇)alkyl; R₂₂ is a hydrogen ora (C₁-C₇)alkyl; R₂₃ and R₂₄ are each independently a hydrogen or a(C₁-C₇)alkyl; R₂₅ is a hydrogen or a (C₁-C₇)alkyl; and R₂₆ and R₂₇ areeach independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be aformyl or a (C₁-C₇)alkylcarbonyl, with the proviso that: when Ar′₁ isthe 3,4-dichlorophenyl group and —A′—Z′ is the 3-methoxybenzyl group,B_(b) is the group B_(1b) of the formula

in which J_(1b) is the group

in which x is one, Ar_(2a) is a phenyl group and X_(1b) is other thanhydrogen, and its salts with mineral or organic acids.
 20. A compoundaccording to any one of claims 1, 2 or 19 of the formula

in which: B′_(b) is a group B′_(1b) of the formula

in which J′_(1b) is a group

in which: x is one; Ar_(2a) is a phenyl which is unsubstituted ormonosubstituted orpolysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, atrifluoromethyl and a methylenedioxy, said substituents being identicalor different; and X′_(1b) is as group selected from: (C₁-C₇)alkyl;—(CH₂)_(m)—OR₄ in which m is one or two and R₄ is a hydrogen or a(C₁-C₇)alkyl; —(CH₂)_(m)—OCOR₅ in which: m is zero and R₅ is a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; or a pyridyl; or m is one or two and R₅ is ahydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; or a pyridyl;—(CH₂)_(m)—OCONH—(C₁-C₇)alkyl in which im is zero, one or two;—O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl; —(CH₂)_(n)—SR₇ in which n is zero or one and R₇ isa hydrogen or a (C₁-C₇)alkyl; —CH₂—S(O)_(j)—(C₁-C₇)alkyl in which j isone or two; NR₈R₉ in which R₈ is a hydrogen or a (C₁-C₇)alkyl and R₉ isa (C₃-C₇)cycloalkylmethyl or a benzyl; or R₈ and R₉, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;—(CH₂)_(p)—NR₁₀R₁₁ in which p is one or two and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a(C₃-C₇)cyclo-alkylmethyl or a benzyl; —NR₁₂COR₁₃ in which R₁₂ is ahydrogen or a (C₁-C₇)alkyl and R₁₃ is a (C₃-C₇)-cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; orR₁₂ and R₁₃ together are a group —(CH₂)_(u)— in which u is three orfour; —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₅is a (C₁-C₄)alkoxy; —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one or two,W₁ is an oxygen atom or a sulfur atom, R₁₄ is a hydrogen or a(C₁-C₇)alkyl and R₁₆ is a hydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or animidazolyl; —(CH₂)₂—NR₁₄COOR₁₇ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁-C₇)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl;—(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is zero, one or two, R₁₄ is a hydrogenor a (C₁-C₇)alkyl and R₁₈ is a (C₁-C₇)alkyl; an amino which is free orsubstituted by one or two (C₁-C₇)alkyls; or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a(C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁-C₇)alkyls, said substituents beingidentical or different; —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀ in which m is zero,one or two, W₁ is an oxygen atom or a sulfur atom, R₁₄ is a hydrogen ora (C₁-C₇)alkyl and R₁₉ and R₂₀ are each independently a hydrogen or a(C₁-C₇)alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; aphenyl; or a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, aphenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁-C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;—(CH₂)_(n)—COOR₂₁ in which n is one and R₂₁ is a hydrogen or a(C₁-C₇)alkyl; —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is zero or one, W₁ isan oxygen atom or a sulfur atom and R₁₉ and R₂₀ are each independently ahydrogen or a (C₁-C₇)-alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl; a(C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; aphenyl; or a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, aphenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁-C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;—CO—NR₂₂—NR₂₃R₂₄ in which R₂₂ is a hydrogen or a (C₁-C₇)alkyl and R₂₃and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl;

in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be a formyl ora (C₁-C₇)alkylcarbonyl; and

and its salts with mineral or organic acids.
 21. A compound according toany one of claims 1, 2, 19 or 20 of the formula

in which: X″_(1b) is a group selected from: —(CH₂)_(p)—NR₁₀R₁₁ in whichp is one and R₁₀ and R₁₁ are each a hydrogen; —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆in which p is one, W₁ is an oxygen atom, R₁₄ is a hydrogen or a(C₁-C₇)alkyl and R₁₆ is a (C₁-C₇)alkyl, preferably an ethyl;—(CH₂)_(m)—NR₁₄COOR₁₇ in which m is zero, R₁₄ is a hydrogen and R₁₇ is a(C₁-C₇)alkyl, preferably an ethyl; and —(CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in whichn is zero, W₁ is an oxygen atom and R₁₉ and R₂₀, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,perhydroazepine and piperazine which is unsubstituted or substituted inthe 4-position by a (C₁-C₄)alkyl, preferably pyrrolidine, and its saltswith mineral or organic acids.
 22. A compound according to claim 1 orclaim 2 of the formula

in which: —Ar′₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; —A′ is adirect bond or a group —CH₂—; —Z′ is as defined above in claim 2; and—B_(c) is a group B_(1c) of the formula

in which J_(1c) is a group in which: x is zero or one; Ar_(2a) is aphenyl which is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a(C₁-C₄)alkyl, a trifluoromethyl and a methylenedioxy, said substituentsbeing identical or different; and X_(1b) is as defined for a compound offormula (I_(b)) in claim 19, and its salts with mineral or organicacids.
 23. A compound according to any one of claims 1, 2 or 22 of theformula

in which: B′_(c) is a group B′_(1c) of the formula

in which J′_(1c) is a group

in which: x is zero or one; Ar_(2a) is a phenyl which is unsubstitutedor monosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkyl, atrifluoromethyl and a methylenedioxy, said substituents being identicalor different; and X′_(1b) is a group selected from: (C₁-C₇)alkyl;—(CH₂)_(m)—OR₄ in which m is one or two and R₄ is a hydrogen or a(C₁-C₇)alkyl; —(CH₂)_(m)—OCOR₅ in which m is zero and R₅ is a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; or a pyridyl; and m is one or two and R₅ is ahydrogen; a (C₁-C₇)alkyl; a (C₃-C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; or a pyridyl;—(CH₂)_(m)—OCONH—(C₁-C₇)alkyl in which m is zero, one or two;—O—CH₂—CH₂—OR₆ in which R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a(C₁-C₇)alkylcarbonyl; —(CH₂)₂—SR₇ in which n is zero or one and R₇ is ahydrogen or a (C₁-C₇)alkyl; —CH₂—S(O)_(j)—(C₁-C₇)alkyl in which j is oneor two; —NR₈R₉ in which R₈ is a hydrogen or a (C₁-C₇)alkyl and R₉ is a(C₃-C₇)cycloalkylmethyl or a benzyl; or R₈ and R₉, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;—(CH₂)_(p)—NR₁₀R₁₁ in which p is one or two, R₁₀ is a hydrogen or a(C₁-C₇)alkyl and R₁₁ is a hydrogen, a (C₁-C₇)alkyl, a(C₃-C₇)cycloalkylmethyl or a benzyl; —NR₁₂COR₁₃ in which R₁₂ is ahydrogen or a (C₁-C₇)alkyl and R₁₃ is a (C₃-C₇)-cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; orR₁₂ and R₁₃ together form a group —(CH₂)_(u) in which u is three orfour; —NR₁₄COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₅is a (C₁-C₄)alkoxy; —(CH₂)_(p)—NR₁₄C(═W₁)R₁₆ in which p is one or two,W₁ is an oxygen atom or a sulfur atom, R₁₄ is a hydrogen or a(C₁-C₇)alkyl and R₁₆ is a hydrogen or a (C₁-C₇)alkyl; a(C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; a benzyl; a vinyl; a pyridyl; a turyl; a thienyl; apyrrolyl; or an imidazolyl; —(CH₂)_(m)—NR₁₄COOR₁₇ in which m is zero,one or two, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₇ is a(C₁-C₇)alkyl or a phenyl; —(CH₂)_(m)—NR₁₄SO₂R₁₈ in which m is zero, oneor two, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₉ is a (C₁-C₇)alkyl;an amino which is free or substituted by one or two (C₁-C₇)alkyls; or aphenyl which is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a (C₁-C₇)alkyl, atrifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a(C₁-C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro andan amino which is free or substituted by one or two (C₁-C₇)alkyls, saidsubstituents being identical or different; —(CH₂)_(m)—NR₁₄C(═W₁)NR₁₉R₂₀in which m is zero, one or two, W₁ is an oxygen atom or a sulfur atom,R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₉ and R₂₀ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₂₀ can also be a(C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a(C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; —(CH₂)_(n)—COOR₂₁ in which n is one and R₂₁ is a hydrogenor a (C₁-C₇)alkyl; (CH₂)_(n)—C(═W₁)NR₁₉R₂₀ in which n is zero or one, W₁is an oxygen atom or a sulfur atom and R₁₉ and R₂₀ are eachindependently a hydrogen or a (C₁-C₇)-alkyl; R₂₀ can also be a(C₃-C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a(C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁-C₇)alkyl substituted by ahydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two(C₁-C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁-C₄)alkyl; —CO—NR₂₂—NR₂₃R₂₄ in which R₂₂ is a hydrogen or a(C₁-C₇)alkyl and R₂₃ and R₂₄ are each independently a hydrogen or a(C₁-C₇)alkyl;

in which R₂₅ is a hydrogen or a (C₁-C₇)alkyl and R₂₆ and R₂₇ are eachindependently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be a formyl ora (C₁-C₇)alkylcarbonyl; and

and its salts with mineral or organic acids.
 24. A compound according toany one of claims 1, 2, 3, 4, 5, 6, 8, 11, 14, 15 and 16 to 23 selectedfrom:1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)-piperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)-propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-piperidinopiperid-1-yl)propyl]piperidine;3-[3-[4-(acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;3-[3-[4-(2-aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;3-[3-(4-acetyl-4-benzylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichloro-phenyl)piperidine;3-[3-[4-(acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(dimethylaminocarbonyl)-4-phenylpiperid-1-yl]propyl]perhydroazepine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenyl-piperid-1-yl]propyl]piperidine;3-[3-[4-(2-acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;3-(3,4-dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-spiro(indoline-3,4′-piperid-1′-yl)propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4′-piperid-1′-yl)]propyl]piperidine;3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(2-thenoyl)piperidine;3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(3-thenoyl)piperidine;3-(3,4-dichlorophenyl)-1-(2-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]pipenidine;3-(3,4-dichlorophenyl)-1-(3-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]pipernidine;3-[3-[4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(ethoxalylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-morpholinopiperid-1-yl)propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methoxycarbonyl)spiro(indoline-3,4′-piperid-1′-yl)]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(N,N-dimethylcarbamoyl)spiro(indoline-3,4′-piperid-1′-yl)]propyl]piperidine;and1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methanesulfonyl)spiro(indoline-3,4′-piperid-1′-yl)]propyl]piperidine,in the form of racemates or one of their (+) or (−) enantiomers, andtheir salts with mineral or organic acids.
 25. Solvates of the compoundsaccording to any one of claims 1 to 24 and their salts.
 26. Method ofpreparing a compound of formula (I) according to claim 1 and its salts,characterized in that: 1) a compound of the formula

in which Ar₁, R₁and R₂ are as defined for a compound of formula (I) inclaim 1 and E is hydrogen or an O-protecting group, is treated: eitherwith a halogenated derivative of the formula Hal—CH₂—A—Z   (III) inwhich Hal is a halogen atom, preferably bromine, and A and Z are asdefined for a compound of formula (I) in claim 1, when it is desired toprepare a compound of formula (I) in which T is a group —CH₂—; or with afinctional derivative of an acid of the formula HO—CO—A—Z   (IIIa) inwhich A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is a group —CO—; or with achloroformate of the formula Cl—COO—A—Z   (IIIb) in which A and Z are asdefined above, when it is desired to prepare a compound of formula (I)in which T is group —COO—; or with an isocyanate of the formulaO═C═N—A—Z   (IIIc) in which A and Z are as defined above, when it isdesired to prepare a compound of formula (I) in which T is a group—CO—NR₃— in which R₃ is hydrogen; or with a carbamoyl chloride of theformula

in which A and Z are as defined above and R′₃ is a (C₁-C₄)alkyl, when itis desired to prepare a compound of formula (I) in which T is —CONR₃— inwhich R₃ is a (C₁-C₄)alkyl; or with a sulfonyl chloride of the formulaCl—SO₂—Z   (IIIe) in which Z is as defined above, when it is desired toprepare a compound of formula (I) in which —T—A— is a group —SO₂—, togive a compound of the formula

2) the O-protecting group, if present, is removed from the compound offormula (IV), by reaction with an acid or a base, to give the alcohol ofthe formula

3) the alcohol (V) is treated with a compound of the formula G—SO₂—Cl  (VI) in which G is a methyl, phenyl, tolyl or trifluoromethyl group,to give a compound of the formula

4) the compound (VII) is reacted: either with a cyclic secondary amineof the formula

in which J′₁ is:

in which Ar₂ and x are as defined for (I) in claim 1 and X′₁ is eitherX₁ as defined for (I), or a precursor of X₁ it being understood thatwhen X′₁ contains a hydroxyl group or an amino group, these groups canbe protected;

in which Ar₂ is as defined for (I) in claim 1;

in which Ar₂ is as defined for (I) in claim 1;

in which Ar₂, is as defined for (I) in claim 1;

in which Ar₂, and Am₁ and r are as defined for (I) in claim 1;

in which Ar₂ and W₂ are as defined for (I) in claim 1; or with a cyclicsecondary amine of the formula

in which J₂ is as defined above for (I) in claim 1; or with a cyclicsecondary amine of the formula

in which J₃ is as defined above for (I) in claim 1; or with a cyclicsecondary amine of the formula

in which W₄ is as defined above for (I) in claim 1; or with a cyclicsecondary amine of the formula

in which W₆, W₇ and W₈ are as defined above for (I) in claim 1; or witha cyclic secondary amine of the formula

in which J₄ is as defined above for (I) in claim 1; or with a compoundof the formula

in which f, g, W₁₂, W₁₃, W₁₄, W₁₅ and W₁₆ are as defined above for (I)in claim 1; or with a cyclic secondary amine of the formula

in which W₁₇, W₁₈, W₁₉ and W₂₀ are as defined above for (I) in claim 1;or with a cyclic secondary amine of the formula

in which J₅ is as defined above for (I) in claim 1; or a cyclicsecondary amine of the formula

in which J′₆ is a group

in which W₂₅ is as defined above for (I) and X′₁ is X₁ as defined for(I) in claim 1, or a precursor of X₁, it being understood that when X′₁contains a hydroxyl group or an amino group, these groups can beprotected; and 5) after deprotection of the hydroxyl groups or aminogroups, if appropriate, or conversion of X′₁ to X₁, if appropriate, theresulting product is optionally converted to one of its salts with amineral or organic acid.
 27. Method of preparing a compound of formula(I) according to claim 1 and its salts, characterized in that: 1′) thenitrogen atom of the compound of formula (II) as defined in claim 25 isprotected to give a compound of the formula

in which Ar₁, R₁ and R₂ are as defined for a compound of formula (I) inclaim 1, E is hydrogen or an O-protecting group and Pr is anN-protecting group such as the trityl, tert-butoxycarbonyl orbenzyloxycarbonyl group; 2′) the O-protecting group, if present, isremoved from the compound of formula (XVII), by reaction with an acid ora base, to give the alcohol of the formula

3′) the alcohol (XVIII) is treated with a compound of formula (VI) asdefined in claim 25 to give a compound of the formula

4′) the compound (XIX) is reacted with a compound of fonnula (VIIIa),(VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi)or (VIIIj) as defined in claim 25 to give a compound of the formula

in which B is as defined for a compound of formula (I) in claim I, itbeing understood that when B contains a hydroxide group or an aminogroup, these groups can be protected; 5′) the protecting group Pr isselectively removed from the compound of formula (XX) to give thecompound of the formula

6′) the compound of formula (XXI) is treated with a compound of formula(III), (IIIa), (IIIb), (IIIc), (IIId) or (IIIe) as defined in claim 25;and 7′) after deprotection of the hydroxyl groups or amino groups, ifappropriate, the resulting product is optionally converted to one of itssalts with a mineral or organic acid.
 28. Method according to claim 27for the preparation of a compound of formula (I^(•)) according to claim4 and its salts, characterized in that: 1^(•)) a compound of the formula

in which G is a methyl, phenyl, tolyl or trifluoromethyl group and Pr isan N-protecting group such as the trityl, fert-butoxycarbonyl orbenzyloxycarbonyl group, is reacted with a compound of the formula

in which J^(•) is as defined for a compound of formula (I^(•)) in claim4, to give a compound of the formula

2^(•)) the protecting group Pr is selectively removed from the compoundof formula (XX^(•)) to give the compound of the formula

3^(•)) the compound of formula (XXI^(•)) is treated with a functionalderivative of an acid of the formula HO—CO—Z^(•)  (III) in which Z^(•)is as defined for a compound of formula (I^(•)) in claim 4; and 4^(•))after deprotection, if appropriate, the resulting product (I^(•)) isoptionally converted to one of its salts with a mineral or organic acid.29. An enantiomer of a compound according to claim 1 of the formula

in which: “*” denotes that the carbon atom carrying this label has thedetermined (+) or (−) absolute configuration; and R₁, R₂, Ar₁, T, A, Zand B are as defined for the compounds of formula (I) in claim 1, andits salts with mineral or organic acids, and their solvates. 30.Pharmaceutical composition comprising, as the active principle, acompound according to any one of claims 1 to 24 or 29 or one of itspharmaceutically acceptable salts and solvates.
 31. Pharmaceuticalcomposition according to claim 30 in the form of a dosage unit in whichthe active principle is mixed with at least one pharmaceuticalexcipient.
 32. Pharmaceutical composition according to claim 31containing 0.5 to 1000 mg of active principle.
 33. Pharmaceuticalcomposition according to claim 32 containing 2.5 to 250 mg of activeprinciple.